U.S. patent application number 13/057599 was filed with the patent office on 2011-08-18 for tricyclic compound.
This patent application is currently assigned to KYOWA HAKKO KIRIN CO., LTD.. Invention is credited to Takeshi Kuboyama, Masahiro Matsubara, Michihiko Suzuki, Tomohiro Tamura, Keiji Uehara, Kimihisa Ueno, Keisuke Yamamoto, Arata Yanagisawa.
Application Number | 20110201640 13/057599 |
Document ID | / |
Family ID | 41663762 |
Filed Date | 2011-08-18 |
United States Patent
Application |
20110201640 |
Kind Code |
A1 |
Yanagisawa; Arata ; et
al. |
August 18, 2011 |
TRICYCLIC COMPOUND
Abstract
Provided is a tricyclic compound having a PPAR .gamma. agonist
activity, which is represented by the general formula (I) wherein Z
represents a single bond or the like, Y represents a hydrogen atom,
lower alkyl optionally having substituent(s) or the like, X
represents a hydrogen atom or the like, A represents aryl or the
like, B and C are the same or different and each represents an
aromatic carbocycle or the like, R.sup.4-R.sup.9 are the same or
different and each represents hydrogen or the like, V represents a
single bond or the like, R.sup.10 and R.sup.11 are the same or
different and each represents hydrogen or the like, or a
pharmaceutically acceptable salt thereof or the like:
##STR00001##
Inventors: |
Yanagisawa; Arata;
(Shizuoka, JP) ; Uehara; Keiji; (Shizuoka, JP)
; Matsubara; Masahiro; (Shizuoka, JP) ; Ueno;
Kimihisa; (Shizuoka, JP) ; Suzuki; Michihiko;
(Shizuoka, JP) ; Kuboyama; Takeshi; (Shizuoka,
JP) ; Yamamoto; Keisuke; (Shizuoka, JP) ;
Tamura; Tomohiro; (Shizuoka, JP) |
Assignee: |
KYOWA HAKKO KIRIN CO., LTD.
Tokyo
JP
|
Family ID: |
41663762 |
Appl. No.: |
13/057599 |
Filed: |
August 6, 2009 |
PCT Filed: |
August 6, 2009 |
PCT NO: |
PCT/JP2009/063957 |
371 Date: |
April 28, 2011 |
Current U.S.
Class: |
514/291 ;
514/303; 514/364; 514/374; 514/381; 514/394; 546/118; 546/89;
548/132; 548/235; 548/250; 548/304.4 |
Current CPC
Class: |
A61K 31/4353 20130101;
A61P 19/02 20180101; C07D 403/10 20130101; C07D 413/10 20130101;
A61P 1/04 20180101; C07D 257/04 20130101; A61P 9/10 20180101; A61P
25/28 20180101; A61P 35/04 20180101; C07D 409/14 20130101; A61K
31/335 20130101; A61K 31/4409 20130101; A61P 35/00 20180101; C07D
235/08 20130101; A61P 9/00 20180101; C07D 471/04 20130101; A61P
3/00 20180101; A61P 3/10 20180101; A61P 15/00 20180101; A61K 31/422
20130101; A61P 17/04 20180101; C07C 255/34 20130101; A61P 17/00
20180101; C07D 235/16 20130101; A61P 9/12 20180101; A61P 25/00
20180101; A61P 25/16 20180101; A61P 43/00 20180101; C07C 255/44
20130101; C07D 413/14 20130101; A61P 3/06 20180101; C07D 405/14
20130101; A61P 17/06 20180101; C07D 413/04 20130101; A61K 31/4184
20130101; A61P 3/04 20180101; A61P 13/12 20180101; A61P 29/00
20180101 |
Class at
Publication: |
514/291 ;
548/304.4; 514/394; 548/250; 514/381; 548/132; 514/364; 546/118;
514/303; 548/235; 514/374; 546/89 |
International
Class: |
A61K 31/4184 20060101
A61K031/4184; C07D 235/16 20060101 C07D235/16; C07D 403/06 20060101
C07D403/06; C07D 413/10 20060101 C07D413/10; A61K 31/4245 20060101
A61K031/4245; C07D 471/04 20060101 C07D471/04; A61K 31/437 20060101
A61K031/437; C07D 413/14 20060101 C07D413/14; A61K 31/41 20060101
A61K031/41; C07D 405/14 20060101 C07D405/14; A61K 31/422 20060101
A61K031/422; C07D 491/044 20060101 C07D491/044; A61K 31/4353
20060101 A61K031/4353; A61P 3/10 20060101 A61P003/10; A61P 9/12
20060101 A61P009/12; A61P 3/04 20060101 A61P003/04; A61P 35/00
20060101 A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 6, 2008 |
JP |
2008-203216 |
Claims
1. A tricyclic compound represented by the general formula (I)
##STR00333## wherein Z represents a single bond, CH.sub.2,
CH.sub.2CH.sub.2, CH.dbd.CH, O, S, CH.sub.2O, OCH.sub.2,
CH.sub.2S(O).sub.n or S(O).sub.nCH.sub.2 wherein n is an integer of
0 to 2, Y represents a hydrogen atom, lower alkyl optionally having
substituent(s), lower alkoxy optionally having substituent(s),
cycloalkyl optionally having substituent(s) or halogen, X
represents a hydrogen atom, lower alkyl, cyano, halogen,
hydroxymethyl, aminomethyl, carboxy, lower alkoxycarbonyl
optionally having substituent(s), carbamoyl, lower alkylcarbamoyl
optionally having substituent(s), di-lower alkylcarbamoyl
optionally having substituent(s), arylcarbamoyl optionally having
substituent(s), lower alkylsulfonylcarbamoyl optionally having
substituent(s), arylsulfonylcarbamoyl optionally having
substituent(s), cycloalkylsulfonylcarbamoyl optionally having
substituent(s), lower alkylaminosulfonylcarbamoyl optionally having
substituent(s), aliphatic heterocyclyl carbonyl optionally having
substituent(s), lower alkanoylaminomethyl optionally having
substituent(s), lower alkylsulfonylaminomethyl optionally having
substituent(s), an aliphatic heterocyclic group optionally having
substituent(s) or an aromatic heterocyclic group optionally having
substituent(s), A represents aryl optionally having substituent(s)
or an aromatic heterocyclic group optionally having substituent(s),
B and C are the same or different and each represents an aromatic
carbocycle or aromatic heterocycle, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8 and R.sup.9 are the same or different and each
represents a hydrogen atom, halogen, hydroxy, lower alkoxy or lower
alkyl, V represents a single bond, O, NR.sup.A wherein R.sup.A
represents a hydrogen atom, lower alkyl optionally having
substituent(s), lower alkanoyl optionally having substituent(s),
lower alkoxycarbonyl optionally having substituent(s), lower
alkylcarbamoyl optionally having substituent(s) or lower
alkylsulfonyl optionally having substituent(s), or S, and R.sup.10
and R.sup.11 are the same or different and each represents a
hydrogen atom or lower alkyl, or a pharmaceutically acceptable salt
thereof.
2. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 1, wherein ##STR00334## represents the
following formula c20-c22 ##STR00335## wherein R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each as defined above,
Y.sup.A represents lower alkyl or cycloalkyl optionally having
substituent(s), X.sup.B represents the following group (b19)-(b24)
##STR00336## wherein R.sup.B-3 represents lower alkyl optionally
having substituent(s) or aryl optionally having substituent(s), A
represents the following group (a38) or (a39) ##STR00337## wherein
R.sup.1A represents lower alkyl optionally having substituent(s),
aryl optionally having substituent(s) or cycloalkyl optionally
having substituent(s), R.sup.L and R.sup.M are the same or
different and each represents a hydrogen atom, halogen, carbamoyl,
lower alkylcarbamoyl optionally having substituent(s), lower alkyl
optionally having substituent(s) or lower alkylsulfonylamino
optionally having substituent(s), V represents a single bond, and
R.sup.10 and R.sup.11 are the same or different and each is a
hydrogen atom or lower alkyl.
3. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 2, wherein ##STR00338## represents the
following formula c20 ##STR00339## wherein R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, X.sup.B, and Y.sup.A are each
as defined above, A is represented by the following group (a38-1)
##STR00340## wherein R.sup.1A-1 represents lower alkyl optionally
having substituent(s) or cycloalkyl optionally having
substituent(s), R.sup.L-1 and R.sup.M-1 are the same or different
and each represents a hydrogen atom, halogen or lower alkyl
optionally having substituent(s).
4. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 2, wherein ##STR00341## represents the
following formula c24 ##STR00342## wherein R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, and Y.sup.A are each as defined
above, X.sup.C is represented by the following group (b20)
##STR00343## R.sup.1A represents lower alkyl optionally having
substituent(s) other than hydroxy, aryl optionally having
substituent(s) or cycloalkyl optionally having substituent(s), and
R.sup.L and R.sup.M are the same or different and each represents a
hydrogen atom, lower alkyl, halogen, carbamoyl or lower
alkylcarbamoyl optionally having substituent(s).
5. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 4, wherein A is represented by the
following group (a38-2) ##STR00344## wherein R.sup.1A-2 represents
lower alkyl optionally having substituent(s) other than hydroxy,
aryl optionally having substituent(s), or cycloalkyl optionally
having substituent(s), R.sup.L-2 and R.sup.M-2 are the same or
different and each represents a hydrogen atom, lower alkyl,
halogen, carbamoyl or lower alkylcarbamoyl optionally having
substituent(s).
6. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 3, wherein X.sup.B is a group selected
from the group consisting of the following formulas (b19), (b20)
and (b22) ##STR00345##
7. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 3, wherein X.sup.B is represented by the
following group (b20) ##STR00346##
8. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 1, wherein ##STR00347## represents the
following formula c7-c9 ##STR00348## wherein R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, and X.sup.B are each as defined
above, and A represents the following formula ##STR00349## wherein
R.sup.C represents a hydrogen atom, halogen, nitro, cyano, formyl,
oxo, hydroxy, lower alkoxy optionally having substituent(s), lower
alkanoyloxy optionally having substituent(s), lower alkyl
optionally having substituent(s), lower alkenyl optionally having
substituent(s), lower alkanoyl optionally having substituent(s),
lower alkoxycarbonyl optionally having substituent(s), lower
alkylsulfonylamino optionally having substituent(s),
--NR.sup.FR.sup.G wherein R.sup.F and R.sup.G are the same or
different and each represents a hydrogen atom, lower alkyl
optionally having substituent(s), lower alkanoyl optionally having
substituent(s) or lower alkoxycarbonyl optionally having
substituent(s), or R.sup.F and R.sup.G form, each together with the
adjacent nitrogen atom, a nitrogen-containing heterocyclic group
optionally having substituent(s), --CONR.sup.HR.sup.I wherein
R.sup.H and R.sup.I are the same or different and each represents a
hydrogen atom, lower alkyl optionally having substituent(s), lower
alkanoyl optionally having substituent(s) or lower alkoxycarbonyl
optionally having substituent(s), or R.sup.H and R.sup.I, form,
together with the adjacent nitrogen atom, a nitrogen-containing
heterocyclic group optionally having substituent(s), aryl
optionally having substituent(s), cycloalkyl optionally having
substituent(s), an aromatic heterocyclic group optionally having
substituent(s) or an aliphatic heterocyclic group optionally having
substituent(s), R.sup.1-2 represents lower alkyl optionally having
substituent(s), cycloalkyl optionally having substituent(s) or
lower alkoxy optionally having substituent(s), R.sup.J represents
aryl optionally having substituent(s), an aromatic heterocyclic
group optionally having substituent(s) (except benzimidazolyl
group) or an aliphatic heterocyclic group optionally having
substituent(s), and V represents a single bond.
9. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 8, wherein ##STR00350## represents the
following formula c17 ##STR00351## wherein X.sup.C, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are each as defined
above, and R.sup.1-2 is lower alkyl optionally having
substituent(s) other than hydroxy.
10. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 8, wherein ##STR00352## is the following
formula c18 ##STR00353## wherein X.sup.D is the following group
(b24) .cndot.-COOH (b24), and R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8 and R.sup.9 are each as defined above.
11. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 8, wherein ##STR00354## is the following
formula c19 ##STR00355## wherein X.sup.E is the following group
(b19) ##STR00356## R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and
R.sup.9 are each as defined above, R.sup.1-2 is lower alkyl, and
R.sup.J is phenyl optionally having a fluorine atom as a
substituent, thienyl, oxazolyl, oxadiazolyl or
5-methyloxazol-2-yl.
12. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 8, wherein X.sup.B is the following
formula (b20) ##STR00357## and R.sup.1-2 is lower alkyl.
13. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 1, wherein X represents a hydrogen atom,
lower alkyl, cyano, halogen, hydroxymethyl, aminomethyl, lower
alkoxycarbonyl optionally having substituent(s), carbamoyl, lower
alkylcarbamoyl optionally having substituent(s), di-lower
alkylcarbamoyl optionally having substituent(s), arylcarbamoyl
optionally having substituent(s), lower alkylaminosulfonylcarbamoyl
optionally having substituent(s), aliphatic heterocyclyl carbonyl
optionally having substituent(s), lower alkanoylaminomethyl
optionally having substituent(s), lower alkylsulfonylaminomethyl
optionally having substituent(s) or any of the following formulas
(b1)-(b16) ##STR00358## ##STR00359## wherein R.sup.B-1 represents
lower alkyl optionally having substituent(s) or cycloalkyl
optionally having substituent(s), R.sup.B-2 represents cycloalkyl
optionally having substituent(s), R.sup.B represents a hydrogen
atom, lower alkyl optionally having substituent(s) or cycloalkyl
optionally having substituent(s), and the broken line is absent or
a single bond.
14. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 1, wherein A is represented by any of
the formulas (a1)-(a34) ##STR00360## ##STR00361## ##STR00362##
##STR00363## ##STR00364## wherein R.sup.1, R.sup.2 and R.sup.3 are
the same or different and each represents a hydrogen atom, lower
alkyl optionally having substituent(s), cycloalkyl optionally
having substituent(s), halogen, lower alkoxy optionally having
substituent(s), lower alkylsulfanyl optionally having
substituent(s), lower alkenyl optionally having substituent(s),
lower alkanoyl optionally having substituent(s), lower
alkoxycarbonyl optionally having substituent(s), carbamoyl, lower
alkylcarbamoyl optionally having substituent(s), di-lower
alkylcarbamoyl optionally having substituent(s), aliphatic
heterocyclyl carbonyl optionally having substituent(s), aryloxy
optionally having substituent(s), aryl optionally having
substituent(s), an aromatic heterocyclic group optionally having
substituent(s), or an aliphatic heterocyclic group optionally
having substituent(s), R.sup.1-1 represents a hydrogen atom, lower
alkenyl optionally having substituent(s), lower alkanoyl optionally
having substituent(s), lower alkoxycarbonyl optionally having
substituent(s), carbamoyl, lower alkylcarbamoyl optionally having
substituent(s), di-lower alkylcarbamoyl optionally having
substituent(s), aliphatic heterocyclyl carbonyl optionally having
substituent(s), aryloxy optionally having substituent(s), aryl
optionally having substituent(s), an aromatic heterocyclic group
optionally having substituent(s), an aliphatic heterocyclic group
optionally having substituent(s) or aralkyloxy optionally having
substituent(s), R.sup.C, R.sup.D and R.sup.E are the same or
different and each is as defined for the aforementioned R.sup.C,
R.sup.K represents cycloalkyl optionally having substituent(s),
halogen, lower alkoxy optionally having substituent(s), lower
alkylsulfanyl optionally having substituent(s), carbamoyl, aryloxy
optionally having substituent(s), aryl optionally having
substituent(s), an aromatic heterocyclic group optionally having
substituent(s), aralkyl optionally having substituent(s), or an
aliphatic heterocyclic group optionally having substituent(s),
R.sup.D-1 represents cycloalkyl optionally having
substituent(s).
15. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 1, wherein V is O, NR.sup.A wherein
R.sup.A is as defined above, or S.
16. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 1, wherein at least one of R.sup.10 and
R.sup.11 is lower alkyl.
17. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 1, wherein ##STR00365## is represented
by any of the following formulas c10-c13 ##STR00366## wherein
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, X and Y are
each as defined above.
18. The tricyclic compound or the pharmaceutically acceptable salt
thereof of claim 1, wherein X is the following formula (b17) or
(b18) ##STR00367##
19. The tricyclic compound or the pharmaceutically acceptable salt
thereof of claim 1, wherein A is a group selected from the group
consisting of the following formulas (a1)-(a14) and (a23)-(a34)
##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.1-1, R.sup.D-1, R.sup.C,
R.sup.D, R.sup.E and R.sup.K are each as defined above, and V is a
single bond.
20. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 1, wherein V is O, NR.sup.A wherein
R.sup.A is as defined above, or S.
21. The tricyclic compound or the pharmaceutically acceptable salt
thereof of claim 1, wherein A represents a group selected from the
group consisting of the following formulas (a15)-(a22),
##STR00373## wherein R.sup.1, R.sup.2 and R.sup.3 are each as
defined above, and V is O or NR.sup.A wherein R.sup.A is as defined
above.
22. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 1, wherein A is the following formula
##STR00374## wherein R.sup.1, R.sup.C and R.sup.D-1 are each as
defined above.
23. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 1, wherein ##STR00375## is a group
selected from the group consisting of the following formulas c1-c3
##STR00376## wherein Y, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8
and R.sup.9 are each as defined above and X.sup.A represents any of
the following formulas (b1)-(b16) ##STR00377## ##STR00378## wherein
R.sup.B-1, R.sup.B-2 and R.sup.B are each as defined above, and the
broken line is absent or a single bond.
24. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 1, wherein ##STR00379## is a group
selected from the group consisting of the following formulas c4-c6
##STR00380## wherein X.sup.A, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8 and R.sup.9 are each as defined above.
25. The tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 1, wherein at least one of R.sup.10 and
R.sup.11 is lower alkyl.
26. A pharmaceutical composition comprising the tricyclic compound
or the pharmaceutically acceptable salt thereof according to claim
1, as an active ingredient.
27. A PPAR .gamma. agonist comprising the tricyclic compound or the
pharmaceutically acceptable salt thereof according to claim 1, as
an active ingredient.
28. A therapeutic and/or prophylactic agent for a disease
associated with PPAR .gamma., which comprises the tricyclic
compound or the pharmaceutically acceptable salt thereof according
to claim 1, as an active ingredient.
29. The agent according to claim 28, wherein the disease associated
with PPAR .gamma. is a disease selected from the group consisting
of type 2 diabetes, impaired glucose tolerance, insulin resistance
syndrome, hypertension, hyperlipidemia, metabolic syndrome,
visceral obesity, obesity, hypertriglyceridemia and tumor.
30. A method of activating PPAR .gamma., comprising administering
the tricyclic compound or the pharmaceutically acceptable salt
thereof according to claim 1.
31. A therapeutic and/or prophylactic method of a disease
associated with PPAR .gamma., comprising administering the
tricyclic compound or the pharmaceutically acceptable salt thereof
according to claim 1.
32. The method according to claim 31, wherein the disease
associated with PPAR .gamma. is a disease selected from the group
consisting of type 2 diabetes, impaired glucose tolerance, insulin
resistance syndrome, hypertension, hyperlipidemia, metabolic
syndrome, visceral obesity, obesity, hypertriglyceridemia and
tumor.
33. Use of the tricyclic compound or the pharmaceutically
acceptable salt thereof according to claim 1, for the manufacture
of a PPAR .gamma. agonist.
34. Use of the tricyclic compound or the pharmaceutically
acceptable salt thereof according to claim 1, for the manufacture
of a therapeutic and/or prophylactic agent for a disease associated
with PPAR .gamma..
35. The use according to claim 34, wherein the disease associated
with PPAR .gamma. is a disease selected from the group consisting
of type 2 diabetes, impaired glucose tolerance, insulin resistance
syndrome, hypertension, hyperlipidemia, metabolic syndrome,
visceral obesity, obesity, hypertriglyceridemia and tumor.
Description
TECHNICAL FIELD
[0001] The present invention relates to a tricyclic compound having
a peroxisome proliferator-activated receptor (PPAR) .gamma. agonist
activity, which is useful as an agent for treating and/or
preventing, for example, type 2 diabetes, impaired glucose
tolerance, insulin resistance syndrome, hypertension,
hyperlipidemia, metabolic syndrome, visceral obesity, obesity,
hypertriglyceridemia, inflammatory skin diseases, inflammatory
diseases, proliferative diseases, inflammatory neuropsychiatric
diseases, angiogenesis and pathological angiogenesis relating to
tumor growth and metastasis, neurodegenerative neuropsychiatric
diseases or the like.
BACKGROUND ART
[0002] Peroxisome proliferator-activated receptor (PPAR) is a
member of the nuclear receptor superfamily of ligand activated
transcription factor. Three subtypes of PPAR, i.e., PPAR .alpha.,
PPAR .gamma., and PPAR .delta., have been cloned from mouse and
human. PPAR is an important nuclear hormone receptor for the
metabolism of carbohydrate and lipid, cell growth and
differentiation, phenotype conversion, apoptosis, angiogenesis,
immunoregulation, and inflammatory reaction. Compounds that
activate PPAR are useful for the treatment or prophylaxis of
various clinical diseases such as metabolic syndrome, obesity,
prediabetes, type 2 diabetes and the other insulin resistance
syndrome, hypertension, atherosclerosis, lipemia, inflammatory skin
diseases such as psoriasis, inflammatory bowel disease, and
inflammatory neurodegenerative diseases such as multiple sclerosis,
Alzheimer's disease etc., proliferative diseases such as benign or
malignant tumor, metastatic tumor or the like, or the like. PPAR
.gamma. specifically plays an important role in adipocyte
differentiation. Hypertrophic adipocytes secrete large amounts of a
cytokine such as TNF-.alpha., and free fatty acid which induce
insulin resistance. On the other hand, thiazolidinedione
derivatives such as pioglitazone, rosiglitazone or the like improve
insulin resistance by activating PPAR .gamma. to decrease
hypertrophic adipocytes by apoptosis, and promoting differentiation
of preadipocytes into small adipocytes having normal function
(non-patent documents 1 and 2). Pioglitazone and rosiglitazone,
which are PPAR .gamma. agonists, have already been clinically used
as therapeutic drugs for diabetes (patent documents 1 and 2).
[0003] PPAR .gamma. agonists are also useful as agents for treating
and/or preventing diseases besides diabetes, such as metabolic
syndrome, obesity, impaired glucose tolerance and other insulin
resistance syndrome, which are prediabetic conditions,
hypertension, atherosclerosis, hyperlipidemia, inflammatory
diseases such as psoriasis or the like, inflammatory bowel disease,
or the like. It has also been reported that it is useful as a
therapeutic and/or prophylactic agent for proliferative diseases
such as benign or malignant tumor, metastatic tumor, or the like
(non-patent documents 3, 4).
[0004] It has been reported that selective partial agonists against
PPAR .gamma. do not accompany side effects such as body weight
increase, adipocyte accumulation or the like, as compared to the
existing full agonists (thiazolidinedione derivative or the like)
(non-patent document 5).
[0005] A tricyclic compound represented by the following formula
(A) and a derivative thereof are known as PPAR
agonists/antagonists/regulators (patent document 3).
##STR00002##
[0006] It is known that a compound represented by the following
formula (B), which is a tricyclic compound, and a derivative
thereof have a superior hypotensive action based on an angiotensin
II receptor antagonistic action (see patent document 4).
##STR00003##
DOCUMENT LIST
Patent Documents
[0007] patent document 1: JP-A-61-267580 [0008] patent document 2:
JP-A-1-131169 [0009] patent document 3: WO2005/105736 [0010] patent
document 4: JP-A-6-228065
Non-Patent Documents
[0010] [0011] non-patent document 1: J. Biol. Chem., 1995, vol.
270, p. 12953 [0012] non-patent document 2: J. Med. Chem., 1996,
vol. 39, p. 665 [0013] non-patent document 3: Oncogen, 2006, vol.
25, p. 2304 [0014] non-patent document 4: Eur. J. Cancer, 2008,
vol. 44, No. 12, p. 1734 [0015] non-patent document 5: Molecular
Endocrinology, 2003, vol. 17, No. 4, p. 662
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0016] An object of the present invention is to provide a novel
tricyclic compound having a PPAR .gamma. agonist activity or a
pharmaceutically acceptable salt thereof and the like. The
tricyclic compound provided by the present invention or a
pharmaceutically acceptable salt thereof is useful as a therapeutic
and/or prophylactic agent for type 2 diabetes, impaired glucose
tolerance, insulin resistance syndrome, hypertension,
hyperlipidemia, metabolic syndrome, visceral obesity, obesity,
hypertriglyceridemia, inflammatory skin diseases (e.g., psoriasis,
atopic dermatitis, seborrheic dermatitis, solar dermatitis etc.),
inflammatory diseases (e.g., rheumatoid arthritis, ulcerative
colitis, Crohn's disease, endometritis etc.), proliferative
diseases (e.g., atherosclerosis, angiostenosis, restenosis, growth
of benign, malignant tumors or metastatic tumor etc.), inflammatory
neuropsychiatric diseases (e.g., multiple sclerosis etc.),
angiogenesis and pathological angiogenesis relating to tumor growth
and tumor metastasis, neurodegenerative neuropsychiatric diseases
(e.g., Alzheimer's disease, Parkinson's disease etc.),
cardiovascular diseases (e.g., arteriosclerosis, cardiac disease,
cerebral apoplexy, renal diseases etc.), or the like.
[0017] Another object of the present invention is to provide a PPAR
.gamma. agonist containing a tricyclic compound as an active
ingredient.
Means of Solving the Problems
[0018] The present invention relates to the following (1)-(45).
(1) A tricyclic compound represented by the general formula (I)
##STR00004##
wherein Z represents a single bond, CH.sub.2, CH.sub.2CH.sub.2,
CH.dbd.CH, O, S, CH.sub.2O, OCH.sub.2, CH.sub.2S(O).sub.n or
S(O).sub.nCH.sub.2 wherein n is an integer of 0 to 2, Y represents
a hydrogen atom, lower alkyl optionally having substituent(s),
lower alkoxy optionally having substituent(s), cycloalkyl
optionally having substituent(s) or halogen, X represents a
hydrogen atom, lower alkyl, cyano, halogen, hydroxymethyl,
aminomethyl, carboxy, lower alkoxycarbonyl optionally having
substituent(s), carbamoyl, lower alkylcarbamoyl optionally having
substituent(s), di-lower alkylcarbamoyl optionally having
substituent(s), arylcarbamoyl optionally having substituent(s),
lower alkylsulfonylcarbamoyl optionally having substituent(s),
cycloalkylsulfonylcarbamoyl optionally having substituent(s), lower
alkylaminosulfonylcarbamoyl optionally having substituent(s),
arylsulfonylcarbamoyl optionally having substituent(s), aliphatic
heterocyclyl carbonyl optionally having substituent(s), lower
alkanoylaminomethyl optionally having substituent(s), lower
alkylsulfonylaminomethyl optionally having substituent(s), an
aliphatic heterocyclic group optionally having substituent(s) or an
aromatic heterocyclic group optionally having substituent(s), A
represents aryl optionally having substituent(s) or an aromatic
heterocyclic group optionally having substituent(s), B and C are
the same or different and each represents an aromatic carbocycle or
aromatic heterocycle, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8
and R.sup.9 are the same or different and each represents a
hydrogen atom, halogen, hydroxy, lower alkoxy or lower alkyl, V
represents a single bond, O, NR.sup.A wherein R.sup.A represents a
hydrogen atom, lower alkyl optionally having substituent(s), lower
alkanoyl optionally having substituent(s), lower alkoxycarbonyl
optionally having substituent(s), lower alkylcarbamoyl optionally
having substituent(s) or lower alkylsulfonyl optionally having
substituent(s), or S, and R.sup.10 and R.sup.11 are the same or
different and each represents a hydrogen atom or lower alkyl, or a
pharmaceutically acceptable salt thereof. (2) The tricyclic
compound or the pharmaceutically acceptable salt thereof according
to (1) wherein
##STR00005##
represents the following formula c20-c22
##STR00006##
wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9
are each as defined above, Y.sup.A represents lower alkyl or
cycloalkyl optionally having substituent(s), X.sup.B represents the
following group (b19)-(b24)
##STR00007##
wherein R.sup.B-3 represents lower alkyl optionally having
substituent(s) or aryl optionally having substituent(s), A
represents the following group (a38) or (a39)
##STR00008##
wherein R.sup.1A represents lower alkyl optionally having
substituent(s), aryl optionally having substituent(s) or cycloalkyl
optionally having substituent(s), R.sup.L and R.sup.M are the same
or different and each represents a hydrogen atom, halogen,
carbamoyl, lower alkylcarbamoyl optionally having substituent(s),
lower alkyl optionally having substituent(s) or lower
alkylsulfonylamino optionally having substituent(s), V represents a
single bond, and R.sup.10 and R.sup.11 are the same or different
and each is a hydrogen atom or lower alkyl. (3) The tricyclic
compound or the pharmaceutically acceptable salt thereof according
to (2) wherein
##STR00009##
represents the following formula c20
##STR00010##
wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.6, R.sup.9,
X.sup.B, and Y.sup.A are each as defined above, A is represented by
the following group (a38-1)
##STR00011##
wherein R.sup.1A-1 represents lower alkyl optionally having
substituent(s) or cycloalkyl optionally having substituent(s),
R.sup.L-1 and R.sup.M-1 are the same or different and each
represents a hydrogen atom, halogen or lower alkyl optionally
having substituent(s). (4) The tricyclic compound or the
pharmaceutically acceptable salt thereof according to (2)
wherein
##STR00012##
represents the following formula c24
##STR00013##
wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.6, R.sup.9, and
Y.sup.A are each as defined above, X.sup.C is represented by the
following group (b20)
##STR00014##
R.sup.1A represents lower alkyl optionally having substituent(s)
other than hydroxy, aryl optionally having substituent(s) or
cycloalkyl optionally having substituent(s), and R.sup.L and
R.sup.M are the same or different and each represents a hydrogen
atom, lower alkyl, halogen, carbamoyl or lower alkylcarbamoyl
optionally having substituent(s). (5) The tricyclic compound or the
pharmaceutically acceptable salt thereof according to (4) wherein A
is represented by the following group (a38-2)
##STR00015##
wherein R.sup.1A-2 represents lower alkyl optionally having
substituent(s) other than hydroxy, aryl optionally having
substituent(s), or cycloalkyl optionally having substituent(s),
R.sup.L-2 and R.sup.M-2 are the same or different and each
represents a hydrogen atom, lower alkyl, halogen, carbamoyl or
lower alkylcarbamoyl optionally having substituent(s). (6) The
tricyclic compound or the pharmaceutically acceptable salt thereof
according to (3) wherein X.sup.B is a group selected from the group
consisting of the following formulas (b19), (b20) and (b22)
##STR00016##
(7) The tricyclic compound or the pharmaceutically acceptable salt
thereof according to (3) wherein X.sup.B is represented by the
following group (b20)
##STR00017##
(8) The tricyclic compound or the pharmaceutically acceptable salt
thereof according to (1) wherein
##STR00018##
represents the following formula c7-c9
##STR00019##
wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, and
X.sup.B are each as defined above, and A represents the following
formula
##STR00020##
wherein R.sup.C represents a hydrogen atom, halogen, nitro, cyano,
formyl, oxo, hydroxy, lower alkoxy optionally having
substituent(s), lower alkanoyloxy optionally having substituent(s),
lower alkyl optionally having substituent(s), lower alkenyl
optionally having substituent(s), lower alkanoyl optionally having
substituent(s), lower alkoxycarbonyl optionally having
substituent(s), lower alkylsulfonylamino optionally having
substituent(s), --NR.sup.FR.sup.G wherein R.sup.F and R.sup.G are
the same or different and each represents a hydrogen atom, lower
alkyl optionally having substituent(s), lower alkanoyl optionally
having substituent(s) or lower alkoxycarbonyl optionally having
substituent(s), or R.sup.F and R.sup.G form, each together with the
adjacent nitrogen atom, a nitrogen-containing heterocyclic group
optionally having substituent(s), --CONR.sup.HR.sup.I wherein
R.sup.H and R.sup.I are the same or different and each represents a
hydrogen atom, lower alkyl optionally having substituent(s), lower
alkanoyl optionally having substituent(s) or lower alkoxycarbonyl
optionally having substituent(s), or R.sup.H and R.sup.I, form,
together with the adjacent nitrogen atom, a nitrogen-containing
heterocyclic group optionally having substituent(s), aryl
optionally having substituent(s), cycloalkyl optionally having
substituent(s), an aromatic heterocyclic group optionally having
substituent(s) or an aliphatic heterocyclic group optionally having
substituent(s), R.sup.1-2 represents lower alkyl optionally having
substituent(s), cycloalkyl optionally having substituent(s) or
lower alkoxy optionally having substituent(s), R.sup.J represents
aryl optionally having substituent(s), an aromatic heterocyclic
group optionally having substituent(s) (except benzimidazolyl
group) or an aliphatic heterocyclic group optionally having
substituent(s), and V is a single bond. (9) The tricyclic compound
or the pharmaceutically acceptable salt thereof according to (8)
wherein
##STR00021##
represents the following formula c17
##STR00022##
wherein X.sup.C, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and
R.sup.9 are each as defined above, and R.sup.1-2 is lower alkyl
optionally having substituent(s) other than hydroxy. (10) The
tricyclic compound or the pharmaceutically acceptable salt thereof
according to (8) wherein
##STR00023##
is the following formula c18
##STR00024##
wherein X.sup.D is the following group (b24)
.cndot.-COOH (b24), and
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are each as
defined above. (11) The tricyclic compound or the pharmaceutically
acceptable salt thereof according to (8) wherein
##STR00025##
is the following formula c19
##STR00026##
is wherein X.sup.E is the following group (b19)
##STR00027##
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are each as
defined above, R.sup.1-2 is lower alkyl, and R.sup.J is phenyl
optionally having a fluorine atom as a substituent, thienyl,
oxazolyl, oxadiazolyl or 5-methyloxazol-2-yl. (12) The tricyclic
compound or the pharmaceutically acceptable salt thereof according
to (8) wherein X.sup.B is the following formula (b20)
##STR00028##
and R.sup.1-2 is lower alkyl. (13) The tricyclic compound or the
pharmaceutically acceptable salt thereof according to (1) wherein X
represents a hydrogen atom, lower alkyl, cyano, halogen,
hydroxymethyl, aminomethyl, lower alkoxycarbonyl optionally having
substituent(s), carbamoyl, lower alkylcarbamoyl optionally having
substituent(s), di-lower alkylcarbamoyl optionally having
substituent(s), arylcarbamoyl optionally having substituent(s),
lower alkylaminosulfonylcarbamoyl optionally having substituent(s),
aliphatic heterocyclyl carbonyl optionally having substituent(s),
lower alkanoylaminomethyl optionally having substituent(s), lower
alkylsulfonylaminomethyl optionally having substituent(s) or any of
the following formulas (b1)-(b16)
##STR00029## ##STR00030##
wherein R.sup.B-1 represents lower alkyl optionally having
substituent(s) or cycloalkyl optionally having substituent(s),
R.sup.B-2 represents cycloalkyl optionally having substituent(s),
R.sup.B represents a hydrogen atom, lower alkyl optionally having
substituent(s) or cycloalkyl optionally having substituent(s), and
the broken line is absent or a single bond. (14) The tricyclic
compound or the pharmaceutically acceptable salt thereof according
to (1) wherein A is represented by any of the formulas
(a1)-(a34)
##STR00031## ##STR00032## ##STR00033## ##STR00034##
##STR00035##
wherein R.sup.1, R.sup.2 and R.sup.3 are the same or different and
each represents a hydrogen atom, lower alkyl optionally having
substituent(s), cycloalkyl optionally having substituent(s),
halogen, lower alkoxy optionally having substituent(s), lower
alkylsulfanyl optionally having substituent(s), lower alkenyl
optionally having substituent(s), lower alkanoyl optionally having
substituent(s), lower alkoxycarbonyl optionally having
substituent(s), carbamoyl, lower alkylcarbamoyl optionally having
substituent(s), di-lower alkylcarbamoyl optionally having
substituent(s), aliphatic heterocyclyl carbonyl optionally having
substituent(s), aryloxy optionally having substituent(s), aryl
optionally having substituent(s), an aromatic heterocyclic group
optionally having substituent(s), or an aliphatic heterocyclic
group optionally having substituent(s), R.sup.1-1 represents a
hydrogen atom, lower alkenyl optionally having substituent(s),
lower alkanoyl optionally having substituent(s), lower
alkoxycarbonyl optionally having substituent(s), carbamoyl, lower
alkylcarbamoyl optionally having substituent(s), di-lower
alkylcarbamoyl optionally having substituent(s), aliphatic
heterocyclyl carbonyl optionally having substituent(s), aryloxy
optionally having substituent(s), aryl optionally having
substituent(s), an aromatic heterocyclic group optionally having
substituent(s), an aliphatic heterocyclic group optionally having
substituent(s) or aralkyloxy optionally having substituent(s),
R.sup.C, R.sup.D and R.sup.E are the same or different and each is
as defined for the aforementioned R.sup.C, R.sup.K represents
cycloalkyl optionally having substituent(s), halogen, lower alkoxy
optionally having substituent(s), lower alkylsulfanyl optionally
having substituent(s), carbamoyl, aryloxy optionally having
substituent(s), aryl optionally having substituent(s), an aromatic
heterocyclic group optionally having substituent(s), aralkyl
optionally having substituent(s), or an aliphatic heterocyclic
group optionally having substituent(s), R.sup.D-1 represent
cycloalkyl optionally having substituent(s). (15) The tricyclic
compound or the pharmaceutically acceptable salt thereof according
to (1) or (14), wherein V is O, NR.sup.A wherein R.sup.A is as
defined above, or S. (16) The tricyclic compound or the
pharmaceutically acceptable salt thereof according to (1) wherein
at least one of R.sup.10 and R.sup.11 is lower alkyl. (17) The
tricyclic compound or the pharmaceutically acceptable salt thereof
according to (1) wherein
##STR00036##
is represented by any of the following formulas c10-c13
##STR00037##
wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, X and
Y are each as defined above. (18) The tricyclic compound or the
pharmaceutically acceptable salt thereof according to any of (1),
(14), (15) and (16), wherein X is the following formula (b17) or
(b18)
##STR00038##
(19) The tricyclic compound or the pharmaceutically acceptable salt
thereof according to any of (1), (13) and (16), wherein A is a
group selected from the group consisting of the following formulas
(a1)-(a14) and (a23)-(a34)
##STR00039## ##STR00040## ##STR00041## ##STR00042##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.1-1, R.sup.D-1, R.sup.C,
R.sup.D, R.sup.E and R.sup.K are each as defined above, and V is a
single bond. (20) The tricyclic compound or the pharmaceutically
acceptable salt thereof according to (13), (14) or (16), wherein V
is O, NR.sup.A wherein R.sup.A is as defined above, or S. (21) The
tricyclic compound or the pharmaceutically acceptable salt thereof
according to any of (1), (13) and (16), wherein A represents a
group selected from the group consisting of the following formulas
(a15)-(a22),
##STR00043##
wherein R.sup.1, R.sup.2 and R.sup.3 are each as defined above, and
V is O or NR.sup.A wherein R.sup.A is as defined above. (22) The
tricyclic compound or the pharmaceutically acceptable salt thereof
according to (1), (13), (15) or (16), wherein A is the following
formula
##STR00044##
wherein R.sup.1, R.sup.C and R.sup.D-1 are each as defined above.
(23) The tricyclic compound or the pharmaceutically acceptable salt
thereof according to any of (1), (14), (15) and (16), wherein
##STR00045##
is a group selected from the group consisting of the following
formulas c1-c3
##STR00046##
wherein Y, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9
are each as defined above and X.sup.A represents any of the
following formulas (b1)-(b16)
##STR00047## ##STR00048##
wherein R.sup.B-1, R.sup.B-2 and R.sup.B are each as defined above,
and the broken line is absent or a single bond. (24) The tricyclic
compound or the pharmaceutically acceptable salt thereof according
to any of (1), (14), (15) and (16), wherein
##STR00049##
is a group selected from the group consisting of the following
formulas c4-c6
##STR00050##
wherein X.sup.A, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and
R.sup.9 are each as defined above. (25) The tricyclic compound or
the pharmaceutically acceptable salt thereof according to any of
(13), (14) and (15), wherein at least one of R.sup.10 and R.sup.11
is lower alkyl. (26) The tricyclic compound or the pharmaceutically
acceptable salt thereof according to any of (14), (15), (16), (17),
(19), (20), (21), (22) and (25), wherein X is the following formula
(b19), (b20) or (b22)
##STR00051##
(27) The tricyclic compound or the pharmaceutically acceptable salt
thereof according to any of (14), (15), (16), (17), (19), (20),
(21), (22) and (25), wherein X is the following formula (b19)
##STR00052##
(28) The tricyclic compound or the pharmaceutically acceptable salt
thereof according to any of (14), (15), (16), (17), (19), (20),
(21), (22) and (25), wherein X is the following formula (b20)
##STR00053##
(29) The tricyclic compound or the pharmaceutically acceptable salt
thereof according to any of (13), (15), (16), (17), (18), (20),
(23), (24), (25), (26), (27) and (28), wherein A is a group
selected from the following formulas (a35)-(a37):
##STR00054##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.C and R.sup.D are each as
defined above. (30) The tricyclic compound or the pharmaceutically
acceptable salt thereof according to any of (13), (15), (16), (17),
(18), (20), (23), (24), (25), (26), (27) and (28), wherein A is the
following formula (a36):
##STR00055##
wherein R.sup.1, R.sup.C and R.sup.D are each as defined above.
(31) The tricyclic compound or the pharmaceutically acceptable salt
thereof according to any of (13), (14), (16), (17), (18), (22),
(23), (24), (25), (26), (27), (28), (29) and (30), wherein V is a
single bond. (32) The tricyclic compound or the pharmaceutically
acceptable salt thereof according to any of (13), (14), (15), (17),
(18), (19), (20), (21), (22), (23), (24), (26), (27), (28), (29),
(30) and (31), wherein R.sup.10 and R.sup.11 are both hydrogen.
(33) The tricyclic compound or the pharmaceutically acceptable salt
thereof according to any of (13), (14), (15), (16), (18), (19),
(20), (21), (22), (25), (26), (27), (28), (30), (31) and (32),
wherein
##STR00056##
is represented by the following formula c14
##STR00057##
wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, and Y
are each as defined above. (34) The tricyclic compound or the
pharmaceutically acceptable salt thereof according to (13), (14),
(15), (16), (18), (19), (20), (21), (22), (25), (26), (27), (28),
(29), (30), (31) or (32), wherein
##STR00058##
is represented by the following formula c15
##STR00059##
wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, and Y
are each as defined above. (35) The tricyclic compound or the
pharmaceutically acceptable salt thereof according to (13), (14),
(15), (16), (18), (19), (20), (21), (22), (25), (26), (27), (29),
(30), (31) or (32), wherein
##STR00060##
is represented by the following formula c16
##STR00061##
wherein Y.sup.B is hydrogen, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, and R.sup.9 are each as defined above. (36) A
pharmaceutical composition comprising the tricyclic compound or the
pharmaceutically acceptable salt thereof according to any of (1) to
(35), as an active ingredient. (37) A PPAR .gamma. agonist
comprising the tricyclic compound or the pharmaceutically
acceptable salt thereof according to any of (1) to (35) as an
active ingredient. (38) A therapeutic and/or prophylactic agent for
a disease associated with PPAR .gamma., which comprises the
tricyclic compound or the pharmaceutically acceptable salt thereof
according to any of (1) to (35), as an active ingredient. (39) The
agent according to (38), wherein the disease associated with PPAR
.gamma. is a disease selected from the group consisting of type 2
diabetes, impaired glucose tolerance, insulin resistance syndrome,
hypertension, hyperlipidemia, metabolic syndrome, visceral obesity,
obesity, hypertriglyceridemia and tumor. (40) A method of
activating PPAR .gamma., comprising administering the tricyclic
compound or the pharmaceutically acceptable salt thereof according
to any of (1) to (35). (41) A therapeutic and/or prophylactic
method of a disease associated with PPAR .gamma., comprising
administering the tricyclic compound or the pharmaceutically
acceptable salt thereof according to any of (1) to (35). (42) The
method according to (41), wherein the disease associated with PPAR
.gamma. is a disease selected from the group consisting of type 2
diabetes, impaired glucose tolerance, insulin resistance syndrome,
hypertension, hyperlipidemia, metabolic syndrome, visceral obesity,
obesity, hypertriglyceridemia and tumor. (43) Use of the tricyclic
compound or the pharmaceutically acceptable salt thereof according
to any of (1) to (35), for the manufacture of a PPAR .gamma.
agonist. (44) Use of the tricyclic compound or the pharmaceutically
acceptable salt thereof according to any of (1) to (35), for the
manufacture of a therapeutic and/or prophylactic agent for a
disease associated with PPAR .gamma.. (45) The use according to
(44), wherein the disease associated with PPAR .gamma. is a disease
selected from the group consisting of type 2 diabetes, impaired
glucose tolerance, insulin resistance syndrome, hypertension,
hyperlipidemia, metabolic syndrome, visceral obesity, obesity,
hypertriglyceridemia and tumor.
Effect of the Invention
[0019] According to the present invention, a novel tricyclic
compound having a PPAR .gamma. agonist activity, which is useful as
a therapeutic and/or prophylactic agent for, for example, type 2
diabetes, impaired glucose tolerance, insulin resistance syndrome,
hypertension, hyperlipidemia, metabolic syndrome, visceral obesity,
obesity, hypertriglyceridemia, inflammatory skin diseases (e.g.,
psoriasis, atopic dermatitis, seborrheic dermatitis, solar
dermatitis etc.), inflammatory diseases (e.g., rheumatoid
arthritis, ulcerative colitis, Crohn's disease, endometritis etc.),
proliferative diseases (e.g., atherosclerosis, angiostenosis,
restenosis, growth of benign tumor, malignant tumor or metastatic
tumor etc.), inflammatory neuropsychiatric diseases (e.g., multiple
sclerosis etc.), angiogenesis and pathological angiogenesis
relating to tumor growth and metastasis, neurodegenerative
neuropsychiatric diseases (e.g., Alzheimer's disease, Parkinson's
disease etc.), cardiovascular diseases (e.g., arteriosclerosis,
cardiac disease, cerebral apoplexy, renal diseases etc.), or the
like, a pharmaceutically acceptable salt thereof and the like are
provided.
[0020] In addition, a PPAR .gamma. agonist containing a tricyclic
compound as an active ingredient is provided.
DESCRIPTION OF EMBODIMENTS
[0021] Hereinafter a compound represented by the general formula
(I) is referred to as compound (I). The same applies to the
compounds of other formula numbers.
[0022] In the definition of each group of the formula (I),
[0023] Examples of lower alkyl, and the lower alkyl moiety of lower
alkoxy, lower alkylsulfanyl, lower alkylsulfonyl, lower
alkanoyloxy, lower alkanoyl, lower alkoxycarbonyl, lower
alkylcarbamoyl, di-lower alkylcarbamoyl, lower
alkylsulfonylcarbamoyl, lower alkylaminosulfonylcarbamoyl, lower
alkanoylaminomethyl, lower alkylsulfonylamino, and lower
alkylsulfonylaminomethyl include straight chain or branched alkyl
having a carbon number of 1-10. More specific examples thereof
include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl,
octyl, nonyl, decyl and the like. Two lower alkyl moieties of
di-lower alkylcarbamoyl may be the same or different.
[0024] Examples of the lower alkenyl include straight chain or
branched alkenyl having 2 to 10 carbon atoms, and more specific
examples thereof include vinyl, allyl, 1-propenyl, butenyl,
pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl and the
like.
[0025] Examples of cycloalkyl and the cycloalkyl moiety of
cycloalkylsulfonylcarbamoyl include cycloalkyl having 3 to 8 carbon
atoms, and more specific examples thereof include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and
the like.
[0026] Examples of aralkyl and the aralkyl moiety of aralkyloxy
include aralkyl having 7 to 16 carbon atoms, and more specific
examples thereof include benzyl, phenethyl, phenylpropyl,
phenylbutyl, phenylpentyl, phenylhexyl, phenylheptyl, phenyloctyl,
phenylnonyl, phenyldecyl, naphthylmethyl, naphthylethyl,
naphthylpropyl, naphthylbutyl, naphthylpentyl, naphthylhexyl,
anthrylmethyl, anthrylethyl and the like.
[0027] Examples of aryl and the aryl moiety of arylcarbamoyl,
arylsulfonylcarbamoyl, and aryloxy include aryl having a carbon
number of 6-14, and more specific examples thereof include phenyl,
naphthyl, azulenyl, anthryl and the like.
[0028] Examples of the aromatic carbocycle include a benzene ring,
a naphthalene ring and the like.
[0029] Examples of the aliphatic heterocyclic group and the
aliphatic heterocyclic group moiety of aliphatic
heterocyclylcarbonyl include a 5-membered or 6-membered monocyclic
aliphatic heterocyclic group comprising at least one atom selected
from a nitrogen atom, an oxygen atom and a sulfur atom, a bicyclic
or tricyclic condensed aliphatic heterocyclic group containing at
least one atom selected from a nitrogen atom, an oxygen atom and a
sulfur atom, wherein 3- to 8-membered rings are condensed, and the
like, and more specific examples thereof include aziridinyl,
azetidinyl, pyrrolidinyl, piperidino, piperidinyl, azepanyl,
1,2,5,6-tetrahydropyridyl, imidazolidinyl, pyrazolidinyl,
piperazinyl, homopiperazinyl, pyrazolinyl, oxiranyl,
tetrahydrofuranyl, tetrahydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl,
oxazolidinyl, morpholino, morpholinyl, thioxazolidinyl,
4,5-dihydrooxadiazolyl, thiomorpholinyl, 2H-oxazolyl,
2H-thioxazolyl, dihydroindolyl, dihydroisoindolyl,
dihydrobenzofuranyl, benzimidazolidinyl, dihydrobenzooxazolyl,
dihydrobenzothioxazolyl, benzodioxolinyl, tetrahydroquinolyl,
tetrahydroisoquinolyl, dihydro-2H-chromanyl, dihydro-1H-chromanyl,
dihydro-2H-thiochromanyl, dihydro-1H-thiochromanyl,
tetrahydroquinoxalinyl, tetrahydroquinazolinyl,
dihydrobenzodioxanyl and the like.
[0030] Examples of the aromatic heterocyclic group include a
5-membered or 6-membered monocyclic aromatic heterocyclic group
containing at least one atom selected from a nitrogen atom, an
oxygen atom and a sulfur atom, a bicyclic or tricyclic condensed
aromatic heterocyclic group containing at least one atom selected
from a nitrogen atom, an oxygen atom and a sulfur atom, wherein 3-
to 8-membered rings are condensed, and the like, and more specific
examples thereof include furyl, thienyl, pyrrolyl, imidazolyl,
pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,
isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl,
benzothiophenyl, benzoxazolyl, benzothiazolyl, isoindolyl, indolyl,
indazolyl, benzimidazolyl, benzotriazolyl, oxazolopyrimidinyl,
thiazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl,
imidazopyridinyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl and the
like.
[0031] Examples of the aromatic heterocycle include thiophene ring,
pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring,
furan ring, pyrrole ring, pyrazole ring, imidazole ring, oxazole
ring, thiazole ring, isoxazole ring, isothiazole ring and the
like.
[0032] Examples of the nitrogen-containing heterocyclic group
formed together with the adjacent nitrogen atom thereto include a
5-membered or 6-membered monocyclic heterocyclic group containing
at least one nitrogen atom (said monocyclic heterocyclic group may
contain other nitrogen atom, oxygen atom or sulfur atom), a
bicyclic or tricyclic condensed heterocyclic group containing at
least one nitrogen atom (said condensed heterocyclic group may
contain other nitrogen atom, oxygen atom or sulfur atom), wherein
3- to 8-membered rings are condensed, and the like, and more
specific examples thereof include aziridinyl, azetidinyl,
pyrrolidinyl, piperidino, azepanyl, pyrrolyl, imidazolidinyl,
imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, piperazinyl,
homopiperazinyl, oxazolidinyl, 2H-oxazolyl, thioxazolidinyl,
2H-thioxazolyl, morpholino, thiomorpholinyl, dihydroindolyl,
dihydroisoindolyl, indolyl, isoindolyl, tetrahydroquinolyl,
tetrahydroisoquinolyl, dihydrobenzooxazolyl,
dihydrobenzothioxazolyl, benzimidazolidinyl, benzimidazolyl,
dihydroindazolyl, indazolyl, benzotriazolyl, pyrrolopyridinyl,
pyrrolopyrimidinyl, imidazopyridinyl, purinyl and the like.
[0033] Halogen means each atom of fluorine, chlorine, bromine or
iodine.
[0034] The substituents of lower alkyl optionally having
substituent(s), lower alkylsulfonyl optionally having
substituent(s), lower alkenyl optionally having substituent(s),
lower alkoxy optionally having substituent(s), lower alkylsulfanyl
optionally having substituent(s), lower alkanoyloxy optionally
having substituent(s), lower alkanoyl optionally having
substituent(s), lower alkoxycarbonyl optionally having
substituent(s), lower alkylcarbamoyl optionally having
substituent(s), di-lower alkylcarbamoyl optionally having
substituent(s), lower alkylsulfonylcarbamoyl optionally having
substituent(s), lower alkylaminosulfonylcarbamoyl optionally having
substituent(s), lower alkylsulfonylamino optionally having
substituent(s), lower alkanoylaminomethyl optionally having
substituent(s) and lower alkylsulfonylaminomethyl optionally having
substituent(s) are the same or different and examples thereof
include 1 to 3 substituents selected from the group consisting of
halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl,
C.sub.3-8 cycloalkyl, an aliphatic heterocyclic group, an aromatic
heterocyclic group, C.sub.1-10 alkoxy, C.sub.3-8 cycloalkoxy,
C.sub.6-14 aryl, C.sub.6-14 aryloxy, C.sub.7-16 aralkyloxy,
C.sub.2-11 alkanoyloxy, C.sub.7-15 aroyloxy, alkylsulfanyl,
--NR.sup.XR.sup.Y wherein R.sup.X and R.sup.Y are the same or
different and each represents a hydrogen atom, C.sub.1-10 alkyl,
C.sub.3-8 cycloalkyl, C.sub.6-14 aryl, an aromatic heterocyclic
group, C.sub.7-16 aralkyl, C.sub.2-11 alkanoyl, C.sub.7-15 aroyl,
C.sub.1-10 alkoxycarbonyl or C.sub.7-16 aralkyloxycarbonyl,
C.sub.2-11 alkanoyl, C.sub.7-15 aroyl, C.sub.1-10 alkoxycarbonyl,
C.sub.6-14 aryloxycarbonyl, C.sub.1-10 alkylsulfonylcarbamoyl,
C.sub.1-10 alkylcarbamoyl, di-C.sub.1-10 alkylcarbamoyl and the
like.
[0035] The substituents of aryl optionally having substituent(s),
aryloxy optionally having substituent(s), aralkyl optionally having
substituent(s), aralkyloxy optionally having substituent(s),
arylcarbamoyl optionally having substituent(s),
arylsulfonylcarbamoyl optionally having substituent (s), and an
aromatic heterocyclic group optionally having substituent (s) are
the same or different and examples thereof include 1 to 3
substituents selected from the group consisting of halogen,
hydroxy, sulfanyl, nitro, cyano, carbamoyl, C.sub.1-10 alkyl,
C.sub.7-16 aralkyl, trifluoromethyl, C.sub.3-8 cycloalkyl,
C.sub.6-14 aryl, halogenated C.sub.6-14 aryl, an aliphatic
heterocyclic group, an aromatic heterocyclic group, C.sub.1-10
alkoxy, C.sub.3-8 cycloalkoxy, C.sub.6-14 aryloxy, C.sub.7-16
aralkyloxy, C.sub.2-11 alkanoyloxy, C.sub.7-15 aroyloxy, C.sub.1-10
alkylsulfanyl, --NR.sup.XR.sup.Y wherein R.sup.X and R.sup.Y are as
defined above, C.sub.2-11 alkanoyl, C.sub.7-15 aroyl, C.sub.1-10
alkoxycarbonyl, C.sub.6-14 aryloxycarbonyl, C.sub.1-10
alkylcarbamoyl, di-C.sub.1-10 alkylcarbamoyl, C.sub.1-10 alkoxy
C.sub.1-10 alkyl, hydroxy C.sub.1-10 alkyl, C.sub.1-10
alkoxycarbonyl C.sub.1-10 alkyl, C.sub.1-10 alkylsulfonylcarbamoyl
C.sub.1-10 alkyl, C.sub.1-10 alkylcarbamoyl C.sub.1-10 alkyl, a
C.sub.1-10 alkyl aromatic heterocyclic group, hydroxy aromatic
heterocyclylcarbonyl, hydroxy C.sub.1-10 alkylcarbamoyl, C.sub.1-10
alkylsulfonylamino, halogenated C.sub.1-10 alkyl and the like.
[0036] The substituents of cycloalkyl optionally having substituent
(s), cycloalkylsulfonylcarbamoyl optionally having substituent (s),
an aliphatic heterocyclic group optionally having substituent (s),
aliphatic heterocyclyl carbonyl optionally having substituent (s)
and a nitrogen-containing heterocyclic group optionally having
substituent (s) which is formed together with the adjacent nitrogen
atom are the same or different and examples thereof include 1 to 3
substituents selected from the group consisting of oxo, halogen,
hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, C.sub.1-10
alkyl, trifluoromethyl, C.sub.3-8 cycloalkyl, C.sub.6-14 aryl, an
aliphatic heterocyclic group, an aromatic heterocyclic group,
C.sub.1-10 alkoxy, C.sub.3-8 cycloalkoxy, C.sub.6-14 aryloxy,
C.sub.7-16 aralkyloxy, C.sub.2-11 alkanoyloxy, C.sub.7-15 aroyloxy,
C.sub.1-10 alkylsulfanyl, --NR.sup.XR.sup.Y (wherein R.sup.X and
R.sup.Y are as defined above), C.sub.2-11 alkanoyl, C.sub.7-15
aroyl, C.sub.1-10 alkoxycarbonyl, C.sub.6-14 aryloxycarbonyl,
C.sub.1-10 alkylcarbamoyl, di-C.sub.1-10 alkylcarbamoyl and the
like.
[0037] Examples of C.sub.1-10 alkyl and the C.sub.1-10 alkyl moiety
of C.sub.1-10 alkoxy, C.sub.2-11 alkanoyloxy, C.sub.1-10
alkylsulfanyl, C.sub.2-11 alkanoyl, C.sub.1-10 alkoxycarbonyl,
C.sub.1-10 alkylsulfonylcarbamoyl, C.sub.1-10 alkylcarbamoyl and
di-C.sub.1-10 alkylcarbamoyl include the groups recited as examples
of the aforementioned lower alkyl. Two C.sub.1-10 alkyl of
di-C.sub.1-10 alkylcarbamoyl may be the same or different.
[0038] The CO.sub.1-10 alkyl moiety of C.sub.1-10 alkoxy of
C.sub.1-10 alkoxy C.sub.1-10 alkyl is, for example, the groups
recited as examples of the aforementioned C.sub.1-10 alkyl, and the
C.sub.1-10 alkyl moiety of C.sub.1-10 alkoxy C.sub.1-10 alkyl is,
for example, a group obtained by removing one hydrogen atom from
the groups recited as examples of the aforementioned C.sub.1-10
alkyl.
[0039] The C.sub.1-10 alkyl moiety of hydroxy C.sub.1-10 alkyl is,
for example, a group obtained by removing one hydrogen atom from
the groups recited as examples of the aforementioned C.sub.1-10
alkyl.
[0040] The C.sub.1-10 alkyl moiety of C.sub.1-10 alkoxycarbonyl of
C.sub.1-10 alkoxycarbonyl C.sub.1-10 alkyl is, for example, the
groups recited as examples of the aforementioned C.sub.1-10 alkyl,
and the C.sub.1-10 alkyl moiety of C.sub.1-10 alkoxycarbonyl
C.sub.1-10 alkyl is, for example, a group obtained by removing one
hydrogen atom from the groups recited as examples of the
aforementioned C.sub.1-10 alkyl.
[0041] The CO.sub.1-10 alkyl moiety of C.sub.1-10
alkylsulfonylcarbamoyl of C.sub.1-10 alkylsulfonylcarbamoyl
C.sub.1-10 alkyl is, for example, the groups recited as examples of
the aforementioned C.sub.1-10 alkyl, and the C.sub.1-10 alkyl
moiety of C.sub.1-10 alkylsulfonylcarbamoyl C.sub.1-10 alkyl is,
for example, a group obtained by removing one hydrogen atom from
the groups recited as examples of the aforementioned C.sub.1-10
alkyl.
[0042] The C.sub.1-10 alkyl moiety of C.sub.1-10 alkylcarbamoyl of
C.sub.1-10 alkylcarbamoyl C.sub.1-10 alkyl is, for example, the
groups recited as examples of the aforementioned C.sub.1-10 alkyl,
and the C.sub.1-10 alkyl moiety of C.sub.1-10 alkylcarbamoyl
C.sub.1-10 alkyl is, for example, a group obtained by removing one
hydrogen atom from the groups recited as examples of the
aforementioned C.sub.1-10 alkyl.
[0043] The halogen moiety of halogenated C.sub.6-14 aryl is, for
example, the groups recited as examples of the aforementioned
halogen, and the C.sub.6-14 aryl moiety of halogenated C.sub.6-14
aryl is, for example, a group obtained by removing one hydrogen
atom from the groups recited as examples of the aforementioned
C.sub.6-14 aryl.
[0044] The C.sub.1-10 alkyl moiety of C.sub.1-10 alkyl aromatic
heterocyclic group is, for example, the groups recited as examples
of the aforementioned C.sub.1-10 alkyl, and the aromatic
heterocyclic group moiety of the C.sub.1-10 alkyl aromatic
heterocyclic group is, for example, a group obtained by removing
one hydrogen atom from the groups recited as examples of the
aforementioned aromatic heterocyclic group.
[0045] The aromatic heterocycle moiety of hydroxy aromatic
heterocyclyl carbonyl is, for example, a group obtained by removing
one hydrogen atom from the groups recited as examples of the
aforementioned aromatic heterocyclic group.
[0046] The C.sub.1-10 alkyl moiety of hydroxy C.sub.1-10
alkylcarbamoyl is, for example, a group obtained by removing one
hydrogen atom from the groups recited as examples of the
aforementioned C.sub.1-10 alkyl.
[0047] The C.sub.1-10 alkyl moiety of C.sub.1-10 alkylsulfonylamino
is, for example, the groups recited as examples of the
aforementioned C.sub.1-10 alkyl.
[0048] The CO.sub.1-10 alkyl moiety of halogenated C.sub.1-10 alkyl
is, for example, a group obtained by removing one hydrogen atom
from the groups recited as examples of the aforementioned
C.sub.1-10 alkyl.
[0049] Examples of C.sub.3-5 cycloalkyl and the cycloalkyl moiety
of C.sub.3-8 cycloalkoxy include the groups recited as examples of
the aforementioned cycloalkyl.
[0050] Examples of C.sub.6-14 aryl and the aryl moiety of
C.sub.6-14 aryloxy, C.sub.7-15 aroyl, C.sub.7-15 aroyloxy and
C.sub.6-14 aryloxycarbonyl include the groups recited as examples
of the aforementioned aryl.
[0051] Examples of C.sub.7-16 aralkyl and the C.sub.7-16 aralkyl
moiety of C.sub.7-16 aralkyloxy and C.sub.7-16 aralkyloxycarbonyl
include the groups recited as examples of the aforementioned
aralkyl.
[0052] Examples of the aliphatic heterocyclic group, the aromatic
heterocyclic group and halogen include the groups recited as
examples of the aforementioned aliphatic heterocyclic group, the
aforementioned aromatic heterocyclic group and the aforementioned
halogen, respectively.
[0053] The pharmaceutically acceptable salt of compound (I)
comprises, for example, pharmaceutically acceptable acid addition
salts, metal salts, ammonium salts, organic amine addition salts,
amino acid addition salts and the like. Examples of the
pharmaceutically acceptable acid addition salt of compound (I)
include inorganic acid salts such as hydrochloride, hydrobromide,
nitrate, sulfate, phosphate or the like, organic acid salts such as
acetate, oxalate, maleate, fumarate, citrate, benzoate,
methanesulfonate etc., or the like. Examples of the
pharmaceutically acceptable metal salts include alkali metal salts
such as sodium salt, potassium salt or the like, alkaline earth
metal salts such as magnesium salt, calcium salt or the like,
aluminum salt, zinc salt or the like. Examples of the
pharmaceutically acceptable ammonium salt include salts of
ammonium, tetramethylammonium or the like. Examples of the
pharmaceutically acceptable organic amine addition salt include
addition salts such as morpholine, piperidine or the like. Examples
of the pharmaceutically acceptable amino acid addition salt include
addition salts such as lysine, glycine, phenylalanine, aspartic
acid, glutamic acid or the like.
[0054] As compound (I), the compounds described in (1)-(35) are
preferable. More preferable specific embodiment is the general
formula (IA-A) or (IA-B) including the substituents represented by
D, Y.sup.X, Z.sup.X, R.sup.1X, R.sup.2X, R.sup.3X, R.sup.4X,
R.sup.5X, R.sup.6X, R.sup.7X, R.sup.8X, R.sup.9X, R.sup.10X,
R.sup.11X, and A.sup.X or any combination of such substituents.
##STR00062##
1) In compound (IA-A), R.sup.4X, R.sup.5X, R.sup.6X, R.sup.7X,
R.sup.8X and R.sup.9X are preferably, for example, a hydrogen atom
or the like, R.sup.1X is preferably, for example, methyl, ethyl,
propyl or the like, more preferably ethyl, propyl or the like,
R.sup.2X is preferably, for example, phenyl, thiophen-2-yl,
oxazol-2-yl or the like, more preferably phenyl, oxazol-2-yl or the
like, R.sup.3X is preferably, for example, methyl or the like,
R.sup.10X, R.sup.11X is preferably a hydrogen atom, methyl, A.sup.X
is preferably, for example, (b20)
##STR00063##
2) In compound (IA-B), Z.sup.X is preferably CH.sub.2CH.sub.2 or
CH.sub.2O, R.sup.4X, R.sup.5X, R.sup.6X, R.sup.7X, R.sup.8X and
R.sup.9X are preferably, for example, a hydrogen atom or the like,
D is CH or N, more preferably CH, R.sup.1X is preferably ethyl,
isopropyl, propyl, tert-butyl, methoxymethyl, cyclopropyl, benzyl,
phenyl, or the like, more preferably propyl, cyclopropyl or the
like, R.sup.2X is preferably a hydrogen atom, methyl, more
preferably a hydrogen atom, R.sup.3X is preferably a hydrogen atom,
methyl, 2-methoxymethyl, chlorine atom, carbamoyl,
2-hydroxyethylcarbamoyl or the like, more preferably chlorine atom,
methyl or the like, R.sup.10X is preferably a hydrogen atom,
methyl, more preferably a hydrogen atom, R.sup.11X is preferably a
hydrogen atom, Y.sup.X is preferably, for example, methyl, ethyl,
propyl, cyclopropyl, more preferably methyl, cyclopropyl, still
more preferably methyl, A.sup.X is preferably, for example, the
above-mentioned formula (b20).
[0055] Furthermore, a compound represented by the general formula
(IA-C)
##STR00064##
wherein R.sup.1X, R.sup.2X, R.sup.3X, R.sup.4X, R.sup.5X, R.sup.6X,
R.sup.7X, R.sup.8X, R.sup.9X, R.sup.10X, R.sup.11X, and A.sup.X are
groups recited as examples in the aforementioned formula
(IA-A),
or (IA-D)
##STR00065##
[0056] wherein D, Y.sup.X, R.sup.1X, R.sup.2X, R.sup.3X, R.sup.4X,
R.sup.5X, R.sup.6X, R.sup.7X, R.sup.8X, R.sup.9X, R.sup.10X,
R.sup.11X, and A.sup.X are groups recited as examples in the
aforementioned formula (IA-b), is more preferable, and the
substituents represented by D, Y.sup.X, Z.sup.X, R.sup.1X,
R.sup.2X, R.sup.3X, R.sup.4X, R.sup.5X, R.sup.6X, R.sup.7X,
R.sup.8X, R.sup.9X, R.sup.10X, R.sup.11X and A.sup.X or any
combination of such substituents are still more preferable.
[0057] The production methods of compound (I) are explained in the
following.
[0058] In the production methods shown below, when the defined
groups change under the conditions of the production methods or are
inappropriate for performing the production methods, the desired
compound can be produced by performing the methods for the
introduction and removal of the protecting groups conventionally
performed in the synthetic organic chemistry (e.g., methods
described in Protective Groups in Organic Synthesis, third edition,
T. W. Greene, John Wiley & Sons Inc., 1999 etc.) or the like.
If necessary, the order of the reaction steps such as substituent
introduction or the like can also be changed.
Production Method 1
[0059] Of compounds (I), compounds (Ia), (Ib) wherein X is cyano or
carboxy can be produced according to the following steps.
##STR00066##
wherein A, B, C, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11, Y and Z are each as defined above, W
represents a leaving group such as a chlorine atom, a bromine atom,
an iodine atom, trifluoromethanesulfonyloxy, methanesulfonyloxy,
benzenesulfonyloxy, p-toluenesulfonyloxy or the like, V.sup.a
represents O, NR.sup.A wherein R.sup.A is as defined above, or S, M
represents lithium, sodium, MgX.sup.1 (X.sup.1 represents a
chlorine atom, a bromine atom or the like) or the like, each of
R.sup.aa and R.sup.bb represents a lower alkyl such as methyl,
ethyl or the like, or aryl such as phenyl or the like.
Step 1
[0060] Compound (III) can be obtained by reacting compound (IIa)
with 1 equivalent-5 equivalents of compound (IIb) in the presence
of 0.1 equivalent--large excess of a base in a solvent at a
temperature between -20.degree. C. and the boiling point of the
solvent to be used for 5 min-120 hr.
[0061] Examples of the base include sodium hydride, potassium
hydride, butyllithium, lithium diisopropylamide (LDA), lithium
bistrimethylsilylamide, sodium bistrimethylsilylamide, sodium
methoxide, potassium ethoxide, potassium tert-butoxide, potassium
carbonate, sodium hydroxide, diazabicycloundecene (DBU),
triethylamine, diisopropylethylamine and the like. Examples of the
solvent include dimethylformamide (DMF), dimethylacetamide (DMA),
N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO),
tetrahydrofuran (THF), acetonitrile and the like, and these can be
used alone or in a mixture.
[0062] Here, compound (IIa) can be obtained by the methods
described in JP-B-2526005, WO2004/052847 (Lilly) or the like, and
compound (IIb) is commercially available or can be obtained by a
known method (e.g., J. Chem. Soc. Perkin Trans. 1), 1992, p. 313,
Synthetic Communications, 1997, vol. 27, p. 1621, Synthesis, 1987,
p. 411) or a method analogous thereto.
Step 2
[0063] Compound (IV) wherein R.sup.10 and R.sup.11 are the same can
be obtained by reacting compound (III) with 1 equivalent--large
excess of a reducing agent or alkyl metal reagent in a solvent at a
temperature between -20.degree. C. and the boiling point of the
solvent to be used for 5 min-120 hr. In addition, compound (IV)
wherein R.sup.10 and R.sup.11 are different can be synthesized by
reacting compound (IV) wherein R.sup.10 and R.sup.11 are both
hydrogen with an oxidant in a solvent to give aldehyde, treating
the aldehyde with an alkyl metal reagent in the same manner as
above to give a product, and reacting the product again with an
oxidant to give ketone, and treating the ketone with an alkyl metal
reagent in the same manner as above.
[0064] Examples of the reducing agent include sodium borohydride,
lithium borohydride, lithium aluminum hydride, diisobutylaluminum
hydride and the like, examples of the alkyl metal reagent include
alkyllithium, alkylmagnesium chloride, alkylmagnesium bromide,
alkylmagnesium iodide, alkylzinc and the like, and examples of the
oxidant include
1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, sulfur
trioxide pyridine complex, pyridinium chlorochromate and the like.
Examples of the solvent include THF, ether, dioxane,
dichloromethane, hexane, toluene and the like, and these can be
used alone or in a mixture.
Step 3
[0065] Compound (V) can be obtained by reacting compound (IV) in
the presence of 1 equivalent--large excess of a halogenating agent
or sulfonylating agent in a solvent or without solvent at a
temperature between -20.degree. C. and the boiling point of the
solvent to be used for 5 min-72 hr. Examples of the halogenating
agent include thionyl chloride; phosphorus tribromide; boron
tribromide; a combination of triphenylphosphine, 2,6-lutidine and
carbon tetrachloride; a combination of triphenylphosphine,
2,6-lutidine and carbon tetrabromide; a combination of
methanesulfonyl chloride and lithium chloride; a combination of
methanesulfonyl chloride and lithium bromide and the like. Examples
of the sulfonylating agent include trifluoromethanesulfonyl
chloride, methanesulfonyl chloride, methanesulfonic acid anhydride,
benzenesulfonyl chloride, p-toluenesulfonyl chloride and the like.
Examples of the solvent include THF, DMF, DMA, dichloromethane,
dichloroethane, acetonitrile and the like, and these can be used
alone or in a mixture.
Step 4
[0066] Compound (Ia) can be obtained by reacting compound (V) with
1 equivalent-5 equivalents of compound (Va) or (Vaa) in the
presence of, where necessary, 1 equivalent--large excess of a base
in a solvent at a temperature between -20.degree. C. and the
boiling point of the solvent to be used for 5 min-120 hr.
[0067] Examples of the base include sodium carbonate, potassium
carbonate, lithium carbonate, cesium carbonate, sodium hydrogen
carbonate, potassium hydrogen carbonate, lithium hydrogencarbonate,
sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium
methoxide, potassium ethoxide, potassium tert-butoxide, sodium
hydride, potassium hydride, butyllithium, lithium diisopropylamide
(LDA), lithium bistrimethylsilylamide, sodium
bistrimethylsilylamide, triethylamine, diisopropylethylamine,
tributylamine, dicyclohexylmethylamine and the like. Examples of
the solvent include DMF, DMA, NMP, DMSO, THF, acetonitrile,
isopropyl alcohol and the like, and these can be used alone or in a
mixture.
[0068] Here, compound (Va) is commercially available or can be
obtained by a known method (e.g., U.S. Pat. No. 5,332,744,
EP-B-400835, JP-A-5-783228 and the like) or a method analogous
thereto.
Step 5
[0069] Compound (Ib) can be obtained by hydrolyzing the nitrile
group, for example, by reacting compound (Ia) in the presence of a
base such as lithium hydroxide, sodium hydroxide, potassium
hydroxide, barium hydroxide or the like in a suitable
water-containing solvent such as a mixed solvent of methanol,
ethanol, ethylene glycol, dioxane, glyme or water at a temperature
between room temperature and the boiling point of the solvent to be
used for 1 hr-120 hr, or by reacting the compound in an aqueous
solution of sulfuric acid, hydrochloric acid, acetic acid or the
like or a mixture of these acids at a temperature between room
temperature and the boiling point of the solvent to be used for 1
hr-120 hr or the like. Alternatively, compound (Ib) can also be
obtained by once obtaining amide and subjecting the amide to the
above-mentioned reaction again.
Production Method 2
[0070] Of compounds (I), compounds (Ic)-(Ig) wherein X is the
following formula (b15), (b19), (b20), (b22) or (b23)
##STR00067##
wherein R.sup.B is as defined above, can be produced according to
the following steps.
##STR00068##
wherein A, B, C, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11, R.sup.B, V, Y and Z are each as
defined above.
Step 6
[0071] Compound (Ic) can be obtained by reacting compound (Ia)
obtained in step 2 with 1 equivalent to 10 equivalents of sodium
azide in a solvent in the presence of 1 equivalent to large excess
of a weak acid for 5 min to 120 hr at a temperature between
-20.degree. C. and the boiling point of the solvent to be used.
[0072] Examples of the weak acid include ammonium chloride,
triethylamine hydrochloride and the like. Examples of the solvent
include DMF, DMA, NMP, DMSO and the like, and these can be used
alone or in a mixture.
[0073] In addition, in another method, compound (Ic) can also be
obtained by reacting compound (Ia) with 1 equivalent to 10
equivalents of sodium azide in a solvent in the presence of 0.01 to
10 equivalents of an additive at a temperature between -10.degree.
C. and the boiling point of the solvent to be used for 1 hr to 120
hr.
[0074] Examples of the additive include tributyltin chloride,
trimethyltin chloride, dibutyltin oxide and the like. Examples of
the solvent include toluene, xylene and the like, and these can be
used alone or in a mixture.
Step 7
[0075] Compound (Iaa) can be obtained by reacting compound (Ia)
with 1 equivalent to large excess of hydroxylamine in a solvent at
a temperature between -20.degree. C. and the boiling point of the
solvent to be used for 5 min to 120 hr.
[0076] As hydroxylamine, for example, an inorganic acid salt such
as hydroxylamine hydrochloride or the like can be used. In this
case, an equivalent of a base such as sodium methoxide or the like
is preferably copresent. Examples of the solvent include methanol,
ethanol, DMF, DMA, DMSO and the like, and these can be used alone
or in a mixture.
Step 8
[0077] Compound (Id) can be obtained by reacting compound (Iaa)
with 1 equivalent--large excess of chlorocarbonate ester in the
presence of 1 equivalent--large excess of a base in a solvent such
as THF, DMF, DMA, toluene, xylene or the like at a temperature
between -20.degree. C. and the boiling point of the solvent to be
used for 5 min-72 hr, and then in a solvent such as THF, DMF, DMA,
toluene, xylene or the like in the presence of, where necessary,
catalytic amount--10 equivalents of a base at a temperature between
-20.degree. C. and the boiling point of the solvent to be used for
5 min-72 hr. The above-mentioned steps can also be performed
sequentially by adding chlorocarbonate ester and a base to the
reaction mixture continuously without isolating the resultant
product.
[0078] Examples of chlorocarbonate ester include methyl
chlorocarbonate, ethyl chlorocarbonate, propyl chlorocarbonate,
phenyl chlorocarbonate and the like.
[0079] Examples of the base include triethylamine, pyridine,
4-dimethylaminopyridine, sodium hydroxide, sodium hydride,
potassium tert-butoxide, sodium methoxide and the like.
Step 9
[0080] Compound (Ie) can be obtained by reacting compound (Iaa)
with 1 equivalent--large excess of N,N'-thiocarbonyldiimidazole in
the presence of 1 equivalent--large excess of a base in a solvent
at a temperature between -20.degree. C. and the boiling point of
the solvent to be used for 5 min-72 hr.
[0081] Examples of the base include triethylamine, pyridine,
4-dimethylaminopyridine, diazabicycloundecene and the like.
Examples of the solvent include THF, 1,4-dioxane, dichloromethane,
chloroform, acetonitrile, acetone and the like, and these can be
used alone or in a mixture.
Step 10
[0082] Compound (If) can be obtained by reacting compound (Iaa)
with 1 equivalent to large excess of N,N'-thiocarbonyldiimidazole
in a solvent in the presence of 1 equivalent to large excess of a
Lewis acid at a temperature between -20.degree. C. and the boiling
point of the solvent to be used for 5 min to 72 hr.
[0083] Examples of Lewis acid include boron trifluoride diethyl
ether complex, stannous chloride, zinc chloride, silica gel and the
like. Examples of the solvent include THF, 1,4-dioxane,
dichloromethane, chloroform, methanol, ethanol and the like, and
these can be used alone or in a mixture.
Step 11
[0084] Compound (Ig) can be obtained by reacting compound (Iaa)
with 1 equivalent--large excess of acid anhydride in the presence
of, where necessary, 1 equivalent--large excess of a base in a
solvent at a temperature between -20.degree. C. and the boiling
point of the solvent to be used for 5 min-72 hr. Examples of the
acid anhydride include acetic anhydride, propionic anhydride,
trifluoroacetic anhydride and the like. Examples of the base
include triethylamine, pyridine, 4-dimethylaminopyridine,
diazabicycloundecene and the like. Examples of the solvent include
THF, 1,4-dioxane, dichloromethane, chloroform, acetonitrile,
acetone, DMF, DMA, DMSO and the like, and these can be used alone
or in a mixture. In another method, Compound (Ig) can be obtained
by reacting compound (Iaa) with 1 equivalent--large excess of ortho
ester in a solvent or without solvent at a temperature between
-20.degree. C. and the boiling point of the solvent to be used for
5 min-72 hr. Examples of the ortho ester include trimethyl
orthoformate, triethyl orthoformate, trimethyl ortho acetate,
triethyl ortho acetate and the like. Examples of the solvent
include THF, 1,4-dioxane, dichloromethane, chloroform,
acetonitrile, acetone, DMF, DMA, DMSO and the like, and these can
be used alone or in a mixture.
Production Method 3
[0085] Of compounds (I), compounds (Ih)-(Ij) wherein X is the
following formula (b26), (b16) or (b17)
##STR00069##
wherein R.sup.B is as defined above, and R.sup.B-4 is lower alkyl
optionally having substituent(s), cycloalkyl optionally having
substituent(s) or aryl optionally having substituent(s), can be
produced according to the following steps.
##STR00070##
wherein A, B C, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11, R.sup.B, R.sup.B-4, V, Y and Z are
each as defined above.
Step 12
[0086] Compound (Ibb) can be obtained by reacting compound (Ib) in
the presence of 1 equivalent-50 equivalents of a condensing agent,
1 equivalent--large excess of hydrazine and, where necessary, a
base in a solvent at a temperature between -20.degree. C. and the
boiling point of the solvent to be used for 5 min-72 hr. Examples
of the condensing agent include N,N'-carbonyldiimidazole,
dicyclohexylcarbodiimide,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the
like. Examples of the base include triethylamine, pyridine,
4-dimethylaminopyridine, diazabicycloundecene and the like.
Examples of the solvent include THF, 1,4-dioxane, dichloromethane,
chloroform, acetonitrile, acetone and the like, and these can be
used alone or in a mixture.
Step 13
[0087] Compound (Ih) can be obtained by reacting compound (Ibb)
with 1 equivalent-50 equivalents of N,N'-carbonyldiimidazole in the
presence of, where necessary, a base in a solvent at a temperature
between -20.degree. C. and the boiling point of the solvent to be
used for 5 min-72 hr. Examples of the base include triethylamine,
pyridine, 4-dimethylaminopyridine, diazabicycloundecene and the
like. Examples of the solvent include THF, 1,4-dioxane,
dichloromethane, chloroform, acetonitrile, acetone and the like,
and these can be used alone or in a mixture.
Step 14
[0088] Compound (Ii) can be obtained by reacting compound (Ibb)
with 1 equivalent--large excess of acid anhydride in the presence
of, where necessary, 1 equivalent--large excess of a base in a
solvent at a temperature between -20.degree. C. and the boiling
point of the solvent to be used for 5 min-72 hr. Examples of the
acid anhydride include acetic anhydride, propionic anhydride,
trifluoroacetic anhydride and the like. Examples of the base
include triethylamine, pyridine, 4-dimethylaminopyridine,
diazabicycloundecene and the like. Examples of the solvent include
THF, 1,4-dioxane, dichloromethane, chloroform, acetonitrile,
acetone, DMF, DMA, DMSO and the like, and these can be used alone
or in a mixture. In another method, compound (Ii) can be obtained
by reacting compound (Ibb) with 1 equivalent--large excess of ortho
ester in a solvent or without solvent at a temperature between
-20.degree. C. and the boiling point of the solvent to be used for
5 min-72 hr. Examples of the ortho ester include trimethyl
orthoformate, triethyl orthoformate, trimethyl ortho acetate,
triethyl ortho acetate and the like. Examples of the solvent
include THF, 1,4-dioxane, dichloromethane, chloroform,
acetonitrile, acetone, DMF, DMA, DMSO and the like, and these can
be used alone or in a mixture.
Step 15
[0089] Compound (Ij) can be obtained by treating compound (Ib) with
1-50 equivalents of a carboxylic acid activator and reacting the
compound with 1-50 equivalents of compound (VI) in the presence of
1-30 equivalents of a base in a solvent at a temperature between
-20.degree. C. and the boiling point of the solvent to be used for
5 min-72 hr.
[0090] Examples of the carboxylic acid activator include
N,N'carbonyldiimidazole (CDI),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) or
hydrochloride thereof, dicyclohexylcarbodiimide (DCC) and the like.
Examples of the solvent include dichloromethane, acetonitrile,
toluene, ethyl acetate, THF, 1,4-dioxane, DMF, NMP and the like,
and these can be used alone or in a mixture. Examples of the base
include diazabicycloundecene, triethylamine,
4-dimethylaminopyridine, N,N-dimethylaniline, pyridine,
N-methylmorpholine and the like. Compound (VI) can be obtained as a
commercially available product.
Production Method 4
[0091] Of compounds (I), a compound wherein R.sup.B is a hydrogen
atom from among the compounds wherein X is the following formula
(b27)-(b31) or (b6)
##STR00071##
wherein R.sup.B is as defined above, is compound (Ic), (Id), (Ie),
(If) or (Ih) synthesized in production method 2 or 3, and a
compound wherein R.sup.B is lower alkyl optionally having
substituent(s) or cycloalkyl optionally having substituent(s) can
be obtained by treating compound (Ic), (Id), (Ie), (If) or (Ih)
synthesized in production method 2 or 3 with R.sup.B-1U wherein U
is a leaving group such as chlorine atom, a bromine atom, an iodine
atom, trifluoromethanesulfonyloxy, methanesulfonyloxy,
benzenesulfonyloxy, p-toluenesulfonyloxy or the like, and R.sup.B-1
is as defined above, and a base. Examples of the base include
sodium hydride, sodium methoxide, potassium tert-butoxide,
potassium carbonate, sodium hydroxide, diazabicycloundecene (DBU),
triethylamine, diisopropylethylamine and the like.
[0092] In another method, the compound can be obtained by reacting
(Ic)-(If), (Ih) with 1 equivalent-5 equivalents of R.sup.B-1OH
wherein R.sup.B-1 is as defined above in the presence of 1
equivalent--large excess of a condensing agent and, where
necessary, 1 equivalent--large excess of a phosphine compound in a
solvent at a temperature between -20.degree. C. and the boiling
point of the solvent to be used for 5 min-72 hr.
[0093] Examples of the condensing agent include diethyl
azodicarboxylate, diisopropyl azodicarboxylate, di(tert-butyl)
azodicarboxylate, (cyanomethylene)trimethylphosphorane,
(cyanomethylene)tributylphosphorane and the like. Examples of the
phosphine compound include triphenylphosphine, tributylphosphine,
polymer supported triphenylphosphine and the like. Examples of the
solvent include THF, DMF, dichloromethane, acetonitrile and the
like, and these can be used alone or in a mixture.
[0094] The functional groups contained in R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, A, B, C, V,
X, Y and Z and the like in compound (I) can also be converted by a
known method (e.g., the method described in Comprehensive. Organic
Transformations 2nd edition, R. C. Larock, Vch Verlagsgesellschaft
Mbh, 1999 and the like) or methods similar thereto.
[0095] The intermediates and the desired compounds in the
above-mentioned respective production methods can be isolated and
purified by applying separation purification methods usually used
in the synthetic organic chemistry such as filtration, extraction,
washing, drying, concentration, recrystallization, various
chromatographies or the like. In addition, intermediates can also
be subjected to a next reaction without particular
purification.
[0096] Some of compounds (I) contain a geometric isomer, a
stereoisomer such as an optical isomer or the like, a tautomer and
the like. The present invention comprises all possible isomers and
mixtures thereof including these.
[0097] When a salt of compound (I) is to be obtained, compound (I)
obtained in the form of a salt can be directly purified. When it is
obtained in a free form, compound (I) may be dissolved or suspended
in a suitable solvent, and an acid or base is added thereto to form
a salt, which may be isolated and purified.
[0098] While compound (I) and pharmaceutically acceptable salts
thereof may exist in the form of adducts with water or various
solvents, these adducts are also comprised in the present
invention.
[0099] Specific examples of compound (I) obtained by the present
invention are shown in Table 1 to Table 15. However, the compound
of the present invention is not limited to them.
TABLE-US-00001 TABLE 1 ##STR00072## Ex. No. A Y X 1 ##STR00073## H
CN 2 ##STR00074## H CO.sub.2H 3 ##STR00075## H CONH.sub.2 4
##STR00076## H ##STR00077## 5 ##STR00078## H ##STR00079## 6
##STR00080## H ##STR00081## 7 ##STR00082## H ##STR00083## 8
##STR00084## H ##STR00085## 9 ##STR00086## H ##STR00087## 10
##STR00088## H ##STR00089## 11 ##STR00090## H ##STR00091## 12
##STR00092## H ##STR00093## 13 ##STR00094## H ##STR00095## 14
##STR00096## H ##STR00097##
TABLE-US-00002 TABLE 2 ##STR00098## Ex. No. A X Y 15 ##STR00099##
##STR00100## Me 16 ##STR00101## ##STR00102## Me 17 ##STR00103##
##STR00104## Me 18 ##STR00105## ##STR00106## Me 19 ##STR00107##
##STR00108## Me 20 ##STR00109## ##STR00110## Me 21 ##STR00111##
##STR00112## Me 22 ##STR00113## ##STR00114## Me 23 ##STR00115##
##STR00116## Me 24 ##STR00117## ##STR00118## Me
TABLE-US-00003 TABLE 3 ##STR00119## Ex. No. A X Y 25 ##STR00120##
Me 26 ##STR00121## ##STR00122## Me 27 ##STR00123## ##STR00124## Me
28 ##STR00125## ##STR00126## Me 29 ##STR00127## ##STR00128## Me 30
##STR00129## ##STR00130## Me 31 ##STR00131## ##STR00132## Me 32
##STR00133## ##STR00134## Me 33 ##STR00135## ##STR00136## Me 34
##STR00137## ##STR00138## Me 35 ##STR00139## ##STR00140## Me 36
##STR00141## ##STR00142## Me
TABLE-US-00004 TABLE 4 ##STR00143## Ex. No. A Y X 37 ##STR00144## H
##STR00145## 38 ##STR00146## H ##STR00147## 39 ##STR00148## H
##STR00149## 40 ##STR00150## H ##STR00151## 41 ##STR00152## H
##STR00153## 42 ##STR00154## H ##STR00155## 43 ##STR00156## H CN 44
##STR00157## H CN 45 ##STR00158## H CN 46 ##STR00159## H
##STR00160##
TABLE-US-00005 TABLE 5 ##STR00161## Ex. No. A Y X 47 ##STR00162## H
CN 48 ##STR00163## H ##STR00164## 49 ##STR00165## H ##STR00166## 50
##STR00167## H CN 51 ##STR00168## H ##STR00169## 52 ##STR00170## H
##STR00171## 53 ##STR00172## H CN 54 ##STR00173## H ##STR00174## 55
##STR00175## H CO.sub.2H 56 ##STR00176## H CONH.sub.2 57
##STR00177## H ##STR00178## 58 ##STR00179## H ##STR00180## 59
##STR00181## H ##STR00182## 60 ##STR00183## H ##STR00184## 61
##STR00185## H ##STR00186## 62 ##STR00187## H ##STR00188## 63
##STR00189## H ##STR00190##
TABLE-US-00006 TABLE 6 ##STR00191## Ex. No. A Y X 64 ##STR00192## H
##STR00193## 65 ##STR00194## H ##STR00195## 66 ##STR00196## H
##STR00197## 67 ##STR00198## H ##STR00199## 68 ##STR00200## H
##STR00201## 69 ##STR00202## H ##STR00203## 70 ##STR00204## H
##STR00205## 71 ##STR00206## H ##STR00207## 72 ##STR00208## H
CN
TABLE-US-00007 TABLE 7 ##STR00209## Ex. No. A X Y 73 ##STR00210##
##STR00211## Me 74 ##STR00212## ##STR00213## Me 75 ##STR00214##
##STR00215## Me 76 ##STR00216## ##STR00217## Me 77 ##STR00218##
##STR00219## Me 78 ##STR00220## ##STR00221## Me
TABLE-US-00008 TABLE 8 ##STR00222## Ex. No. A Y X 79 ##STR00223## H
##STR00224## 80 ##STR00225## H ##STR00226## ##STR00227## Ex. No. A
X Y 81 ##STR00228## ##STR00229## H 82 ##STR00230## ##STR00231##
H
TABLE-US-00009 TABLE 9 ##STR00232## Ex. No. A R Y X 83 ##STR00233##
Me H ##STR00234## 84 ##STR00235## Me H ##STR00236## 85 ##STR00237##
Me H ##STR00238## 86 ##STR00239## n-Pr H ##STR00240## 87
##STR00241## Me H ##STR00242## 88 ##STR00243## Me H ##STR00244## 89
##STR00245## Me H ##STR00246##
TABLE-US-00010 TABLE 10 ##STR00247## Ex. No. A Y X 90 ##STR00248##
H ##STR00249## 91 ##STR00250## H ##STR00251## 92 ##STR00252## H
##STR00253## 93 ##STR00254## H ##STR00255## 94 ##STR00256## H
##STR00257## 95 ##STR00258## H ##STR00259##
TABLE-US-00011 TABLE 11 ##STR00260## Ex. No. A X Y 96 ##STR00261##
##STR00262## Me 97 ##STR00263## ##STR00264## Me 98 ##STR00265##
##STR00266## Me 99 ##STR00267## ##STR00268## Me 100 ##STR00269##
##STR00270## Me 101 ##STR00271## ##STR00272## Me 102 ##STR00273##
##STR00274## Me 103 ##STR00275## ##STR00276## Me
TABLE-US-00012 TABLE 12 ##STR00277## Ex. No. A X Y 104 ##STR00278##
##STR00279## H 105 ##STR00280## ##STR00281## H 106 ##STR00282##
##STR00283## H 107 ##STR00284## ##STR00285## H 108 ##STR00286##
##STR00287## H 109 ##STR00288## ##STR00289## H 110 ##STR00290##
##STR00291## ##STR00292## 111 ##STR00293## ##STR00294##
##STR00295## 112 ##STR00296## ##STR00297## ##STR00298## 113
##STR00299## ##STR00300## ##STR00301## 114 ##STR00302##
##STR00303## ##STR00304## 115 ##STR00305## ##STR00306##
##STR00307##
TABLE-US-00013 TABLE 13 ##STR00308## Ex. No. A X Y 116 ##STR00309##
##STR00310## Me
TABLE-US-00014 TABLE 14 ##STR00311## Ex. No. A X Y 117 ##STR00312##
##STR00313## Me 118 ##STR00314## ##STR00315## Me 119 ##STR00316##
##STR00317## Me 120 ##STR00318## ##STR00319## Me ##STR00320## Ex.
No. A X Y 121 ##STR00321## ##STR00322## Me
TABLE-US-00015 TABLE 15 ##STR00323## Ex. No. A X Y 122 ##STR00324##
##STR00325## Me 123 ##STR00326## ##STR00327## Me ##STR00328## Ex.
No. A X Y 124 ##STR00329## ##STR00330## Me 125 ##STR00331##
##STR00332## Me
[0100] Next, the pharmacological action of the representative
compound (I) is specifically explained by Test Examples.
Test Example 1
PPAR .gamma. Activation Action Based on Transactivation Assay of
PPAR .gamma. by Transient Gene Transfer
[0101] The agonist activity of compound (I) to PPAR .gamma. was
determined by a transactivation assay method using a chimeric
nuclear receptor of a DNA binding region of a yeast transcription
factor GAL4 and a PPAR .gamma. ligand binding region. Specifically,
the PPAR .gamma. agonist activity of compound (I) was evaluated by
the following method based on the method of Lehmann et al. (J Biol
Chem., 1995, vol. 270, page 12953).
[0102] HEK293EBNA cells cultured in Dulbecco's Modified Eagle
medium (Invitrogen) containing 10 v/v % fetal calf serum
(Invitrogen) were used. 30 mL of the above-mentioned cells
(density: 1.times.10.sup.5 cells/mL) were inoculated in a 10
cm.sup.2 culture dish (Iwaki Glass), and cultured overnight. Using
SuperFect Transfection Reagent (QIAGEN), a plasmid expressing a
GAL4-PPAR .gamma. chimeric nuclear receptor fusing 174-475 amino
acids, which are human PPAR .gamma. ligand binding region, and
1-147 amino acids, which are GAL4 DNA binding region, and a
reporter plasmid expressing a GAL4 responsive luciferase were
transiently introduced into the cells at a proportion of 4:1. After
5 hr from transfection, the cells were detached from the culture
dish, and the detached cells (density: 2.times.10.sup.4 cells/mL)
were inoculated by 100 .mu.L in each well of a 96 well white plate
(SUMITOMO BAKELITE), and cultured overnight. The medium was
removed, compound (I) diluted in various concentrations with
serum-free Dulbecco's Modified Eagle medium was added by 100 .mu.L,
and the mixture was reacted under a 5% carbon dioxide gas stream
(5% CO.sub.2) at 37.degree. C. for 24 hr. On the other hand, as a
positive control, 10 .mu.mol/L of pioglitazone (100 .mu.L) was
added, and the mixture was reacted under a 5% carbon dioxide gas
stream (5% CO.sub.2) at 37.degree. C. for 24 hr. As a substrate of
luciferase, 100 .mu.L of Steady-Glo (Promega) was added to each
well and the mixture was thoroughly stirred. Immediately
thereafter, the chemical luminescence due to luciferase was
measured using TopCount NTX (Packard).
[0103] The agonist activity (activity rate (%)) of compound (I) to
PPAR .gamma. was calculated according to the following formula, as
a relative activity when the agonist activity on addition of
pioglitazone (10 .mu.mol/L) was 100%.
activity rate ( % ) = ( luminescence intensity with addition of
compound ( I ) ) - ( luminescence intensity without addition of
compound ( I ) ) ( luminescence intensity with addition of
pioglitazone 10 mol / L ) - ( luminescence intensity without
addition of compound ( I ) ) .times. 100 ##EQU00001##
[0104] The activity rate at which compound (I) shows the maximum
activity is referred as efficacy and the concentration showing 50%
activity rate of the efficacy was calculated as EC.sub.50 value.
The results are shown in Table 16.
TABLE-US-00016 TABLE 16 EC.sub.50 value compound No. (nmol/L) 5 399
7 791 8 175 17 30 19 6.4 21 40 26 17 27 2.6 30 9.8 33 26 35 2.4 37
412 50 352 54 54 55 39 67 156 70 156 76 328 85 27 87 60 95 31 96 13
100 20 110 16 114 11 115 36 116 12 119 314
[0105] From the above-mentioned results, compound (I) and a
pharmaceutically acceptable salt thereof of the present invention
are considered to have a PPAR .gamma. agonist activity.
Accordingly, compound (I) and a pharmaceutically acceptable salt
thereof of the present invention are expected to be agents for
treating and/or preventing various diseases related to PPAR
.gamma., such as type 2 diabetes, impaired glucose tolerance,
insulin resistance syndrome, hypertension, hyperlipidemia,
metabolic syndrome, visceral obesity, obesity,
hypertriglyceridemia, inflammatory skin diseases (e.g., psoriasis,
atopic dermatitis, seborrheic dermatitis, solar dermatitis etc.),
inflammatory diseases (e.g., rheumatoid arthritis, ulcerative
colitis, Crohn's disease, endometritis etc.), proliferative
diseases (e.g., atherosclerosis, angiostenosis, restenosis, growth
of benign, malignant or metastatic tumor etc.), inflammatory
neuropsychiatric diseases (e.g., multiple sclerosis etc.),
angiogenesis and pathological angiogenesis related to tumor growth
and metastasis, neurodegenerative neuropsychiatric diseases (e.g.,
Alzheimer's disease, Parkinson's disease etc.), cardiovascular
diseases (e.g., arteriosclerosis, cardiac disease, cerebral
apoplexy, renal diseases etc.), or the like.
Test Example 2
Blood Glucose- and Lipid-Lowering Action in Diabetes Mouse
[0106] Test compound was orally administered to db/db mouse
(6-week-old, female), a model of spontaneous type 2 diabetes, at a
dose of 30 mg/kg/day once a day for 6 days. A solvent (0.5%
methylcellulose solution) was administered to the control group.
After 7 days from the administration, glucose and triglycelide in
plasma were measured.
[0107] A part of compound (I) of the present invention was
evaluated as the above-mentioned test compound. It was confirmed
that these compounds remarkably suppressed an increase of serum
glucose and triglycelide, and compound (I) was confirmed to have a
glucose- and lipid-lowering actions in the diabetes model in this
Experiment.
Test Example 3
Ameliorating Action on Impaired Glucose Tolerance and Insulin
Resistance in Type 2 Diabetic Rats
[0108] A test compound is repeatedly administered orally to Zucker
obese rat with type 2 diabetes, once a day for 4 weeks at a dose of
3 mg/kg. A solvent (0.5% methylcellulose solution) is administered
to the control group in a similar manner. After 4 weeks of
administration, an oral glucose tolerance test is performed as
shown below. In addition, plasma insulin level is measured under
full feeding condition.
[0109] Oral glucose tolerance test: After rat is fasted overnight,
a glucose solution is orally administered at a dose of 2 g/kg.
Blood samples are collected from the rat tail vein at 30 min, 60
min and 120 min after administration of the glucose solution, and
the blood glucose level is measured.
[0110] While compound (I) or pharmaceutically acceptable salts
thereof can be administered alone as they are, generally, they are
desirably provided as various pharmaceutical preparations. In
addition, such pharmaceutical preparations are used for animals and
humans.
[0111] The pharmaceutical preparation relating to the present
invention can contain, as an active ingredient, compound (I) or a
pharmaceutically acceptable salt thereof alone or as a mixture with
an active ingredient for any other treatment. Moreover, the
pharmaceutical preparation can be produced by mixing the active
ingredient with one or more kinds of pharmaceutically acceptable
carriers (e.g., diluent, solvent, excipient or the like) according
to any method well known in the technical field of pharmacy.
[0112] As the administration route, a route most effective for the
treatment is desirably employed, which may be an oral or parenteral
route such as intravenous route or the like.
[0113] The dosage form may be, for example, tablet, injection or
the like.
[0114] A form suitable for oral administration, such as tablet or
the like, can be produced by using an excipient such as lactose or
the like, a disintegrant such as starch or the like, a lubricant
such as magnesium stearate or the like, a binder such as
hydroxypropylcellulose or the like.
[0115] A form suitable for parenteral administration, such as
injection or the like, can be produced by using a diluent such as a
salt solution, a glucose solution or a mixture of salt solution and
a glucose solution or the like, or a solvent or the like.
[0116] While the dose and administration frequency of compound (I)
or a pharmaceutically acceptable salt thereof varies depending on
the mode of administration, age and body weight of patients, nature
and severity of the symptom to be treated or the like, it is
generally within the range of 0.01 to 1000 mg, preferably 0.05 to
100 mg, for oral administration to an adult, which is administered
at once or in several portions a day. In the case of parenteral
administration such as intravenous administration or the like,
0.001 to 1000 mg, preferably 0.01 to 100 mg, is administered to an
adult at once or in several portions a day. However, these doses
and administration frequencies vary depending on the aforementioned
various conditions.
The present invention is explained in more detail in the following
by Examples and Reference Examples, which are not to be construed
as limitative.
[0117] The proton nuclear magnetic resonance spectrum (.sup.1H NMR)
used in the Examples and Reference Examples were measured at 270
MHz or 300 MHz, and exchanging protons may not be clearly observed
depending on the compound and measurement conditions. The
indication of the multiplicity of the signals is conventional,
where br means an apparently broad signal.
Example 1
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cycl-
ohepten-5-ylidene]acetonitrile (Compound 1)
[0118]
(E)-2-(2-Bromomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yli-
dene)acetonitrile (648 mg, 2.00 mmol) obtained in Reference Example
B1 and 2-propylbenzimidazole (385 mg, 2.40 mmol) were dissolved in
DMA (2 mL), potassium carbonate (553 mg, 4.00 mmol) was added, and
the mixture was stirred at room temperature for 14 hr. Water was
added to the mixture, and the mixture was extracted with ethyl
acetate. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (chloroform/methanol=97/3) to give the title
compound (compound 1) (778 mg, 96%).
[0119] ESI-MS m/z: 404 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.01 (t, J=7.4 Hz, 3H), 1.85-1.90 (m, 2H), 2.79 (t, J=7.6
Hz, 2H), 3.06 (br s, 4H), 5.29 (s, 2H), 5.67 (s, 1H), 6.79-6.88 (m,
2H), 7.11-7.35 (m, 7H), 7.43 (dd, J=7.3, 1.7 Hz, 1H), 7.76 (d,
J=7.3 Hz, 1H).
Example 2
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cycl-
ohepten-5-ylidene]acetic acid (Compound 2)
[0120]
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a-
,d]cyclohepten-5-ylidene]acetonitrile (260 mg, 0.64 mmol) obtained
in Example 1 was dissolved in ethanol (2.5 mL), 10 mol/L aqueous
sodium hydroxide solution (1 mL) was added, and the mixture was
stirred under reflux for 24 hr. The mixture was neutralized with
hydrochloric acid, and extracted with ethyl acetate. The organic
layer was washed with brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography
(chloroform/methanol=90/10) to give the title compound (compound 2)
(243 mg, 89%).
[0121] ESI-MS m/z: 423 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.98 (t, J=7.3 Hz, 3H), 1.80-1.85 (m, 2H), 2.78 (t, J=7.7
Hz, 2H), 3.11 (br s, 4H), 5.26 (s, 2H), 6.20 (s, 1H), 6.73 (s, 1H),
6.82 (d, J=8.1 Hz, 1H), 7.10-7.27 (m, 8H), 7.73 (d, J=7.3 Hz,
1H).
Example 3
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cycl-
ohepten-5-ylidene]acetamide (Compound 3)
[0122]
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a-
,d]cyclohepten-5-ylidene]acetonitrile (404 mg, 1.00 mmol) obtained
in Example 1 was dissolved in ethanol (8 ml), 2 mol/L aqueous
sodium hydroxide solution (2 mL) was added, and the mixture was
stirred at 70.degree. C. for 2 days. Water was added to the
mixture, and the mixture was extracted with chloroform. The organic
layer was washed with 2 mol/L aqueous sodium hydroxide solution and
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. Ethyl acetate was added to the residue, and
the mixture was filtered to give the title compound (compound 3)
(279 mg, 66%).
[0123] ESI-MS m/z: 422 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.94 (t, J=7.3 Hz, 3H), 1.73-1.78 (m, 2H), 2.79 (t, J=7.4
Hz, 2H), 3.02 (br s, 4H), 5.42 (s, 2H), 6.16 (s, 1H), 6.80 (d,
J=7.9 Hz, 1H), 6.91 (s, 1H), 7.04-7.23 (m, 7H), 7.36-7.39 (m, 1H),
7.54-7.60 (m, 1H).
Example 4
(E)-2-(2-Propylbenzimidazol-1-yl)methyl-5-(1H-tetrazol-5-yl)methylene-10,1-
1-dihydro-5H-dibenzo[a,d]cycloheptene (Compound 4)
[0124]
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a-
,d]cyclohepten-5-ylidene]acetonitrile (200 mg, 0.496 mmol) obtained
in Example 1 was dissolved in toluene (5 ml), trimethylsilylazide
(1.3 ml, 9.92 mmol) and dibutyltin oxide (123 mg, 0.496 mmol) were
added, and the mixture was stirred at 90.degree. C. for 24 hr. The
mixture was concentrated under reduced pressure, and the residue
was purified by silica gel column chromatography
(chloroform/methanol=99/1) to give the title compound (compound 4)
(111 mg, 50%).
[0125] ESI-MS m/z: 447 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.93 (t, J=7.4 Hz, 3H), 1.75 (m, 2H), 2.79 (t, J=7.4 Hz,
2H), 2.89 (m, 2H), 3.36 (m, 2H), 5.43 (s, 2H), 6.78 (s, 1H),
6.80-7.28 (m, 8H), 7.32-7.44 (m, 2H), 7.56 (m, 1H).
Example 5
(E)-2-(2-Propylbenzimidazol-1-yl)methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiaz-
ol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 5)
[0126]
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a-
,d]cyclohepten-5-ylidene]acetonitrile (467 mg, 1.16 mmol) obtained
in Example 1 was dissolved in ethanol (11 mL), hydroxylamine (50%
aqueous solution, 2.13 mL, 34.7 mmol) was added, and the mixture
was heated under reflux for 16 hr, and concentrated under reduced
pressure. The obtained residue was dissolved in DMF (5.5 mL),
pyridine (112 .mu.L, 1.39 mmol) and ethyl chlorocarbonate (133
.mu.L, 1.39 mmol) were added at 0.degree. C., and the mixture was
stirred at room temperature for 1 hr. Ethyl acetate and saturated
aqueous sodium hydrogen carbonate solution were added to the
mixture. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The obtained residue was dissolved in toluene (11 mL),
potassium tert-butoxide (195 mg, 1.74 mmol) was added, and the
mixture was stirred at room temperature for 15 min. Ethyl acetate
was added to the mixture, and the organic layer was washed with 5%
aqueous citric acid solution, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography
(chloroform/methanol=99/1) to give the title compound (compound 5)
(295 mg, 55%).
[0127] ESI-MS m/z: 463 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.93 (t, J=7.4 Hz, 3H), 1.75 (m, 2H), 2.78 (t, J=7.4 Hz,
2H), 2.82 (m, 2H), 3.25 (m, 2H), 5.43 (s, 2H), 6.32 (s, 1H), 6.83
(d, J=7.3 Hz, 1H), 6.96 (s, 1H), 7.00-7.40 (m, 8H), 7.56 (m,
1H).
Example 6
(E)-2-(2-Propylbenzimidazol-1-yl)methyl-5-(4-methyl-5-oxo-4,5-dihydro-1,2,-
4-oxadiazol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 6)
[0128]
(E)-2-(2-Propylbenzimidazol-1-yl)methyl-5-(5-oxo-4,5-dihydro-1,2,4--
oxadiazol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(69 mg, 0.15 mmol) obtained in Example 5 and methanol (30 .mu.l,
0.75 mmol) were dissolved in THF (1 mL), polymer-supported
triphenylphosphine (150 mg, 0.45 mmol) and di-tert-butyl
azodicarboxylate (104 mg, 0.45 mmol) were added at 0.degree. C.,
and the mixture was stirred at room temperature for 1 hr. The
mixture was filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=7/3 to 0/10) to give the title
compound (compound 6) (65 mg, 92%).
[0129] ESI-MS m/z: 477 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.02 (t, J=7.3 Hz, 3H), 1.86-1.92 (m, 2H), 2.79-2.82 (m,
2H), 2.84 (s, 3H), 3.10 (br s, 4H), 5.31 (s, 2H), 6.31 (s, 1H),
6.81 (s, 1H), 6.90 (d, J=7.9 Hz, 1H), 7.11-7.30 (m, 7H), 7.37 (d,
J=7.9 Hz, 1H), 7.76-7.77 (m, 1H).
Example 7
(E)-2-(2-Propylbenzimidazol-1-yl)methyl-5-(5-oxo-4,5-dihydro-1,3,4-oxadiaz-
ol-2-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 7)
[0130] [step 1]
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyc-
lohepten-5-ylidene]acetic acid (130 mg, 0.31 mmol) obtained in
Example 2 was dissolved in THF (1.5 mL), N,N'-carbonyldiimidazole
(80 mg, 0.49 mmol) was added, and the mixture was stirred at room
temperature for 10 min. Hydrazine monohydrate (60 .mu.L, 1.24 mmol)
was added to the reaction mixture, and the mixture was stirred at
room temperature for 30 min. Water was added to the mixture, and
the mixture was extracted with ethyl acetate. The organic layer was
washed with brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (chloroform/methanol=90/10) to
give
(E)-[2-(2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyc-
lohepten-5-ylidene]acetohydrazide (172 mg) quantitatively.
[0131] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.01 (t, J=7.5 Hz, 3H),
1.85-1.90 (m, 2H), 2.76-2.81 (m, 2H), 3.02 (br s, 4H), 3.74 (d,
J=3.7 Hz, 2H), 5.28 (s, 2H), 6.18 (s, 1H), 6.35 (s, 1H), 6.72 (s,
1H), 6.85-6.87 (m, 1H), 7.12-7.31 (m, 8H), 7.75-7.76 (m, 1H).
[step 2]
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenz-
o[a,d]cyclohepten-5-ylidene]acetohydrazide (67 mg, 0.15 mmol)
obtained in step 1 was dissolved in dichloromethane (1.5 mL),
N,N'-carbonyldiimidazole (75 mg, 0.46 mmol) was added, and the
mixture was stirred at room temperature for 2 hr. Water was added
to the mixture, and the mixture was extracted with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate/methanol=95/5) to give the title compound (compound 7) (52
mg, 73%).
[0132] ESI-MS m/z: 463 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.94 (t, J=7.4 Hz, 3H), 1.74-1.79 (m, 2H), 2.79 (t, J=7.4
Hz, 2H), 2.82 (br s, 2H), 3.32 (br s, 2H), 5.43 (s, 2H), 6.37 (s,
1H), 6.80 (d, J=7.6 Hz, 1H), 6.94 (s, 1H), 7.09-7.17 (m, 4H),
7.25-7.40 (m, 4H), 7.57-7.58 (m, 1H).
Example 8
(E)-2-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-5-(5-thio-
xo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d-
]cycloheptene (Compound 8)
[0133]
(E)-[2-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-1-
0,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile
(JP-B-2526005; 220 mg, 0.53 mmol) was dissolved in ethanol (5 mL),
hydroxylamine (50% aqueous solution, 0.48 mL, 7.63 mmol) was added,
and the mixture was heated under reflux for 16 hr, and concentrated
under reduced pressure. The obtained residue was dissolved in
acetonitrile (5 mL), N,N'-thiocarbonyldiimidazole (141 mg, 0.79
mmol) and DBU (315 .mu.L, 2.11 mmol) were added, and the mixture
was stirred at room temperature for 2 hr. Ethyl acetate was added
to the mixture, and the organic layer was washed with 5% aqueous
citric acid solution, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (chloroform/methanol=95/5) to give
the title compound (compound 8) (67 mg, 26%).
[0134] ESI-MS m/z: 494 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.34 (t, J=7.5 Hz, 3H), 2.58 (s, 3H), 2.65 (s, 3H),
2.70-2.97 (m, 2H), 2.80 (q, J=7.5 Hz, 2H), 3.20-3.36 (m, 2H),
5.40-5.50 (m, 2H), 6.22 (br s, 1H), 6.82-6.85 (m, 2H), 6.90-6.94
(m, 1H), 7.09 (d, J=7.3 Hz, 1H), 7.20 (d, J=7.9 Hz, 1H), 7.30-7.45
(m, 3H).
Example 9
(E)-2-(2-Propylbenzimidazol-1-yl)methyl-5-(1,2,4-oxadiazol-3-yl)methylene--
10,11-dihydro-5H-dibenzo[a,d]cycloheptene (Compound 9)
[0135] [step 1]
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyc-
lohepten-5-ylidene]acetonitrile (166 mg, 0.41 mmol) obtained in
Example 1 was dissolved in ethanol (4 mL), hydroxylamine (50%
aqueous solution, 1.26 mL, 20.0 mmol) was added, and the mixture
was heated under reflux for 14 hr, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (chloroform/methanol=90/10) to give
(E)-[2-(2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo-
[a,d]cyclohepten-5-ylidene]-N-hydroxyacetamidine (190 mg)
quantitatively.
[0136] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.99 (t, J=7.3 Hz, 3H),
1.86 (dd, J=15.1, 7.6 Hz, 2H), 2.75-3.50 (m, 4H), 2.78 (dd, J=9.0,
6.4 Hz, 2H), 4.34 (s, 2H), 5.24 (s, 2H), 6.14 (s, 1H), 6.67 (s,
1H), 6.81 (d, J=8.1 Hz, 1H), 7.12-7.30 (m, 9H), 7.76 (d, J=7.7 Hz,
1H).
[step 2] To
(E)-[2-(2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyc-
lohepten-5-ylidene]-N-hydroxyacetamidine (65 mg, 0.149 mmol)
obtained in step 1 was added triethyl orthoformate (1 mL), and the
mixture was stirred at 80.degree. C. for 2 hr. The mixture was
concentrated under reduced pressure, and the residue was purified
by silica gel column chromatography (hexane/ethyl acetate=80/20 to
0/100) to give the title compound (compound 9) (28 mg, 42%).
[0137] ESI-MS m/z: 447 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.02 (t, J=7.3 Hz, 3H), 1.86-1.91 (m, 2H), 2.78-2.81 (m,
2H), 3.02-3.48 (m, 4H), 5.29 (s, 2H), 6.76-6.88 (m, 3H), 7.06-7.26
(m, 7H), 7.40 (d, J=8.1 Hz, 1H), 7.76-7.77 (m, 1H), 8.48 (s,
1H).
Example 10
(E)-2-(2-Propylbenzimidazol-1-yl)methyl-5-(5-trifluoromethyl-1,2,4-oxadiaz-
ol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 10)
[0138]
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a-
,d]cyclohepten-5-ylidene]-N-hydroxyacetamidine (70 mg, 0.16 mmol)
obtained in Example 9, step 1 was dissolved in dichloromethane (1
mL), triethylamine (67 .mu.L, 0.48 mmol) and trifluoroacetic
anhydride (68 .mu.l, 0.48 mmol) were added, and the mixture was
stirred at room temperature for 4 hr. Water was added to the
mixture, and the mixture was extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/ethyl
acetate=90/10 to 50/50) to give the title compound (compound 10)
(41 mg, 49%).
[0139] ESI-MS m/z: 515 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.02 (t, J=7.2 Hz, 3H), 1.80-1.96 (m, 2H), 2.72-3.48 (m,
4H), 2.80 (t, J=8.0 Hz, 2H), 5.29 (s, 2H), 6.71 (s, 1H), 6.77 (s,
1H), 6.87 (d, J=7.9 Hz, 1H), 7.06-7.30 (m, 7H), 7.38 (d, J=7.9 Hz,
1H), 7.76 (d, J=7.2 Hz, 1H).
Example 11
(E)-2-(2-Propylbenzimidazol-1-yl)methyl-5-(1,3,4-oxadiazol-2-yl)methylene--
10,11-dihydro-5H-dibenzo[a,d]cycloheptene (Compound 11)
[0140] To
(E)-[2-(2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenz-
o[a,d]cyclohepten-5-ylidene]acetohydrazide (27 mg, 0.062 mmol)
obtained in Example 7, step 1 was added triethyl orthoformate (0.5
mL), and the mixture was stirred at 120.degree. C. for 20 hr. The
mixture was concentrated under reduced pressure, and the residue
was purified by silica gel column chromatography (hexane/ethyl
acetate=70/30 to 0/100) to give the title compound (compound 11)
(26 mg, 93%).
[0141] ESI-MS m/z: 447 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.02 (t, J=7.4 Hz, 3H), 1.85-1.91 (m, 2H), 2.78-2.82 (m,
2H), 2.80-3.40 (m, 4H), 5.29 (s, 2H), 6.75 (s, 1H), 6.84 (s, 1H),
6.89 (d, J=7.9 Hz, 1H), 7.08-7.32 (m, 7H), 7.38 (d, J=7.9 Hz, 1H),
7.75-7.77 (m, 1H), 8.10 (d, J=0.7 Hz, 1H).
Example 12
N-{(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]c-
yclohepten-5-ylidene]acetyl}methanesulfonamide (Compound 12)
[0142]
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a-
,d]cyclohepten-5-ylidene]acetic acid (60 mg, 0.14 mmol) obtained in
Example 2 was dissolved in DMF (0.6 mL), N,N'-carbonyldiimidazole
(92 mg, 0.57 mmol) was added, and the mixture was stirred at room
temperature for 1 hr. Methanesulfonamide (68 mg, 0.71 mmol) and DBU
(106 .mu.L, 0.71 mmol) were added to the reaction mixture, and the
mixture was stirred at 80.degree. C. for 2 hr. Water and 5% aqueous
citric acid solution were added to the mixture, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. Ethyl acetate was added to the residue, and
the mixture was filtered to give the title compound (compound 12)
(29 mg, 41%).
[0143] ESI-MS m/z: 500 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.04 (t, J=7.3 Hz, 3H), 1.90-1.95 (m, 2H), 2.83-3.30 (m,
4H), 3.05 (t, J=7.9 Hz, 2H), 3.17 (s, 3H), 5.39 (s, 2H), 6.22 (s,
1H), 6.80 (s, 1H), 6.87 (d, J=8.1 Hz, 1H), 7.20-7.45 (m, 8H), 7.94
(d, J=7.7 Hz, 1H).
Example 13
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cycl-
ohepten-5-ylidene]ethanol (Compound 13)
[0144]
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a-
,d]cyclohepten-5-ylidene]acetic acid (80 mg, 0.189 mmol) obtained
in Example 2 was dissolved in 1,2-dimethoxyethane (0.7 mL),
N-methylmorpholine (62 .mu.L, 0.567 mmol) and isobutyl
chlorocarbonate (49 .mu.L, 0.378 mmol) were added, and the mixture
was stirred at room temperature for 1 hr. The reaction mixture was
filtered, and the filtrate was added to a solution (0.6 mL) of
sodium borohydride (36 mg, 0.945 mmol) in water at 0.degree. C.,
and the mixture was stirred for 10 min. Water was added to the
mixture, and the mixture was extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography
(chloroform/methanol=95/5) to give the title compound (compound 13)
(43 mg, 55%).
[0145] ESI-MS m/z: 407 (M-H).sup.-; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.01 (t, J=7.6 Hz, 3H), 1.87 (m, 2H), 2.79 (t, J=7.6 Hz,
2H), 2.71-3.42 (m, 4H), 4.19 (d, J=8.6 Hz, 2H), 5.27 (s, 2H), 6.03
(t, J=6.8 Hz, 1H), 6.72 (s, 1H), 6.73-6.89 (m, 2H), 6.98-7.34 (m,
7H), 7.76 (d, J=6.3 Hz, 1H).
Example 14
N-{(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]c-
yclohepten-5-ylidene]ethyl}methanesulfonamide (Compound 14)
[0146]
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a-
,d]cyclohepten-5-ylidene]ethanol (50 mg, 0.122 mmol) obtained in
Example 13 was dissolved in THF (1 mL), phthalimide (27 mg, 0.183
mmol), polymer-supported triphenylphosphine (102 mg, 0.305 mmol)
and di-tert-butyl azodicarboxylate (70 mg, 0.305 mmol) were added,
and the mixture was stirred at room temperature for 1 hr. The
mixture was filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=70/30 to 50/50) to give imide
(51 mg, 52%). The obtained imide (42 mg, 0.078 mmol) was dissolved
in ethanol (1.4 mL), hydrazine monohydrate (76 .mu.L, 1.56 mmol)
was added, and the mixture was stirred at room temperature for 1.5
hr. Water was added to the mixture, and the mixture was extracted
with ethyl acetate. The organic layer was washed with brine, dried
over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (chloroform/methanol=95/5 to 90/10) to give amine
(13 mg, 41%). The obtained amine (13 mg, 0.032 mmol) was dissolved
in dichloromethane (1 ml), pyridine (15 .mu.L, 0.19 mmol) and
methanesulfonyl chloride (7 .mu.L, 0.10 mmol) were added at
0.degree. C., and the mixture was stirred at room temperature for
15 hr. Water was added to the mixture, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (chloroform/methanol=95/5) to give the title
compound (compound 14) (5 mg, 32%).
[0147] ESI-MS m/z: 486 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.01 (t, J=7.3 Hz, 3H), 1.83-1.88 (m, 2H), 2.70-3.35 (m,
4H), 2.79 (t, J=7.7 Hz, 2H), 2.88 (s, 3H), 3.78-3.80 (m, 2H), 4.40
(t, J=5.9 Hz, 1H), 5.27 (s, 2H), 5.89 (t, J=7.0 Hz, 1H), 6.71 (s,
1H), 6.80 (d, J=8.1 Hz, 1H), 7.01-7.25 (m, 8H), 7.75 (d, J=7.7 Hz,
1H).
Example 15
(Z)-2-(Benzimidazol-1-yl)methyl-5-[1-(1H-tetrazol-5-yl)ethylidene]-10,11-d-
ihydro-5H-dibenzo[a,d]cycloheptene (Compound 15)
[0148] [step 1]
(Z)-2-(2-Hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene-
)propiononitrile (500 mg, 1.82 mmol) obtained in Reference Example
B3 was dissolved in THF (19 mL), 2,6-lutidine (1.27 ml, 10.9 mmol),
lithium bromide (0.947 g, 10.9 mmol) and methanesulfonic anhydride
(0.791 g, 4.54 mmol) were added, and the mixture was stirred at
room temperature for 16 hr. Ethyl acetate was added to the mixture,
and the organic layer was washed with brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure to give
a residue.
[0149] Benzimidazole (236 mg, 2.00 mmol) was dissolved in DMF (2.8
mL), potassium carbonate (1.25 g, 9.04 mmol) was added, and the
mixture was stirred for 15 min. To this mixture was added a
solution of the residue obtained above in DMF (7 mL), and the
mixture was stirred at room temperature for 2 hr. Ethyl acetate was
added to the mixture, and the organic layer was washed with brine,
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=7/3 to 4/6) to give
(Z)-2-[2-(benzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohept-
en-5-ylidene]propiononitrile (536 mg, 79%).
[0150] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.02 (s, 3H), 2.81 (m,
2H), 3.29 (m, 2H), 5.32 (s, 2H), 6.89 (s, 1H), 7.06 (m, 1H),
7.13-7.34 (m, 7H), 7.42 (d, J=7.9 Hz, 1H), 7.81 (m, 1H), 7.93 (s,
1H).
[step 2] Using
(Z)-2-[2-(benzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohept-
en-5-ylidene]propiononitrile (253 mg, 0.674 mmol) obtained in step
1 and in the same manner as in Example 4, the title compound
(compound 15) (131 mg, 46%) was obtained.
[0151] ESI-MS m/z: 419 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.03 (s, 3H), 2.77 (m, 2H), 3.25 (m, 2H), 5.35 (s, 2H),
6.57 (d, J=7.9 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 7.06 (s, 1H),
7.10-7.30 (m, 6H), 7.40 (m, 1H), 7.61 (m, 1H), 8.29 (s, 1H).
Example 16
(Z)-2-(Benzimidazol-1-yl)methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3--
yl)ethylidene]-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (Compound
16)
[0152] Using
(Z)-2-[2-(benzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohept-
en-5-ylidene]propiononitrile (280 mg, 0.746 mmol) obtained in
Example 15, step 1 and in the same manner as in Example 5, the
title compound (compound 16) (55 mg, 17%) was obtained.
[0153] ESI-MS m/z: 435 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 1.93 (s, 3H), 2.75 (m, 2H), 3.26 (m, 2H), 5.39 (s, 2H),
6.90-7.28 (m, 9H), 7.44 (m, 1H), 7.62 (m, 1H), 8.33 (s, 1H).
Example 17
(Z)-2-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-5-[1-(1H-tetrazol-5-yl)et-
hylidene]-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (Compound
17)
[0154] [step 1] Using 4-methyl-2-propylbenzimidazole (EP400835; 369
mg, 2.12 mmol) instead of benzimidazole, and in the same manner as
in Example 15, step 1,
(Z)-2-[2-(4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibe-
nzo[a,d]cyclohepten-5-ylidene]propiononitrile (580 mg, 63%) was
obtained.
[0155] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.99 (t, J=7.3 Hz, 3H),
1.71-1.83 (m, 2H), 2.01 (s, 3H), 2.79 (s, 3H), 2.78 (m, 4H), 3.25
(m, 2H), 5.27 (s, 2H), 6.73 (s, 1H), 6.92-7.32 (m, 8H), 7.38 (d,
J=7.9 Hz, 1H).
[step 2] Using
(Z)-2-[2-(4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibe-
nzo[a,d]cyclohepten-5-ylidene]propiononitrile (290 mg, 0.672 mmol)
obtained in step 1 and in the same manner as in Example 4, the
title compound (compound 17) (168 mg, 53%) was obtained.
[0156] ESI-MS m/z: 475 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.88 (t, J=7.2 Hz, 3H), 1.65 (m, 2H), 2.03 (s, 3H), 2.55
(s, 3H), 2.77 (m, 2H), 2.70 (t, J=7.6 Hz, 2H), 3.35 (m, 2H), 5.29
(s, 2H), 6.46-6.59 (m, 2H), 6.81-7.29 (m, 8H).
Example 18
(Z)-2-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-5-[1-(5-oxo-4,5-dihydro-1-
,2,4-oxadiazol-3-yl)ethylidene]-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 18)
[0157] Using
(Z)-2-[2-(4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibe-
nzo[a,d]cyclohepten-5-ylidene]propiononitrile (290 mg, 0.672 mmol)
obtained in Example 17, step 1 and in the same manner as in Example
5, the title compound (compound 18) (115 mg, 35%) was obtained.
[0158] ESI-MS m/z: 491 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.88 (t, J=7.4 Hz, 3H), 1.66 (m, 2H), 1.94 (s, 3H), 2.50
(s, 3H), 2.70 (m, 2H), 2.72 (t, J=7.6 Hz, 2H), 3.25 (m, 2H), 5.35
(s, 2H), 6.71 (d, J=7.6 Hz, 1H), 6.81-7.03 (m, 4H), 7.04-7.29 (m,
5H), 12.15 (br s, 1H).
Example 19
(Z)-2-(4-Chloro-2-cyclopropylbenzimidazol-1-yl)methyl-5-[1-(5-oxo-4,5-dihy-
dro-1,2,4-oxadiazol-3-yl)ethylidene]-10,11-dihydro-5H-dibenzo[a,d]cyclohep-
tene (Compound 19)
[0159] [step 1] Using 4-chloro-2-cyclopropylbenzimidazole (769 mg,
3.99 mmol) obtained in Reference Example A1 instead of
benzimidazole, and in the same manner as in Example 15 step 1,
(Z)-2-[2-(4-chloro-2-cyclopropylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-
-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (630 mg, 635%)
was obtained.
[0160] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.05 (m, 2H), 1.29 (m,
2H), 1.88 (m, 1H), 2.02 (s, 3H), 2.79 (m, 2H), 3.25 (m, 2H), 5.41
(s, 2H), 6.76 (s, 1H), 6.99-7.32 (m, 8H), 7.40 (d, J=7.9 Hz,
1H).
[step 2] Using
(Z)-2-[2-(4-chloro-2-cyclopropylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-
-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (231 mg, 0.513
mmol) obtained in step 1 and in the same manner as in Example 5,
the title compound (compound 19) (154 mg, 59%) was obtained.
[0161] ESI-MS m/z: 509 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.92-1.08 (m, 4H), 1.94 (s, 3H), 2.20 (m, 1H), 2.72 (m,
2H), 3.29 (m, 2H), 5.52 (s, 2H), 6.82-7.30 (m, 9H), 7.40 (d, J=7.9
Hz, 1H).
Example 20
(E)-8-(2-Ethyl-4-phenylimidazol-1-yl)methyl-11-[1-(1H-tetrazol-5-yl)ethyli-
dene]-6,11-dihydrodibenzo[b,e]oxepine (Compound 20)
[0162] [step 1] 2-Ethyl-4-phenylimidazole (Tetrahedron Lett. 2001,
p 7079; 192 mg, 1.12 mmol) was dissolved in DMF (4.8 mL), potassium
carbonate (0.700 g, 5.07 mmol) was added, and the mixture was
stirred for 15 min. To this mixture was added
(E)-2-(8-chloromethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propionon-
itrile (300 mg, 1.01 mmol) obtained in Reference Example B5, and
the mixture was stirred at 60.degree. C. for 3 hr. Ethyl acetate
was added to the mixture, and the organic layer was washed with
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate=9/1 to 6/4) to give
(E)-2-[8-(2-ethyl-4-phenylimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]ox-
epin-11-ylidene]propiononitrile (434 mg, 99%).
[0163] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.32 (t, J=7.6 Hz, 3H),
2.26 (s, 3H), 2.70 (q, J=7.6 Hz, 2H), 4.80 (d, J=12.7 Hz, 1H), 5.12
(s, 2H), 5.45 (d, J=12.7 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 6.92 (d,
J=7.4 Hz, 1H), 7.01-7.30 (m, 6H), 7.35 (t, J=7.7 Hz, 2H), 7.47 (d,
J=7.9 Hz, 1H), 7.76 (d, J=7.3 Hz, 2H).
[step 2] Using
(E)-2-[8-(2-ethyl-4-phenylimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]ox-
epin-11-ylidene]propiononitrile (200 mg, 0.463 mmol) obtained in
step 1 and in the same manner as in Example 4, the title compound
(compound 20) (66 mg, 30%) was obtained.
[0164] ESI-MS m/z: 475 (M-H).sup.-; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.07 (t, J=7.5 Hz, 3H), 2.39 (s, 3H), 2.50 (q, J=7.5 Hz,
2H), 4.59 (d, J=12.8 Hz, 1H), 4.94 (s, 2H), 5.54 (d, J=12.8 Hz,
1H), 6.75-6.97 (m, 5H), 7.02 (s, 1H), 7.15-7.36 (m, 5H), 7.56-7.65
(m, 2H).
Example 21
(E)-8-(2-Ethyl-4-phenylimidazol-1-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-
-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine
(Compound 21)
[0165] Using
(E)-2-[8-(2-ethyl-4-phenylimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]ox-
epin-11-ylidene]propiononitrile (230 mg, 0.530 mmol) obtained in
Example 20, step 1 and in the same manner as in Example 5, the
title compound (compound 21) (48 mg, 18%) was obtained.
[0166] ESI-MS m/z: 491 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.29 (t, J=7.6 Hz, 3H), 2.26 (s, 3H), 2.67 (q, J=7.6 Hz,
2H), 4.78 (d, J=12.8 Hz, 1H), 5.11 (s, 2H), 5.52 (d, J=12.8 Hz,
1H), 6.84 (d, J=8.2 Hz, 1H), 6.93 (t, J=7.4 Hz, 1H), 6.95-7.35 (m,
9H), 7.70-7.80 (m, 2H).
Example 22
(E)-8-(3-Chlorophenoxy)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-y-
l)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine (Compound 22)
[0167] [step 1] Using 3-chlorophenol (143 mg, 1.12 mmol) instead of
2-ethyl-4-phenylimidazole, and in the same manner as in Example 20,
step 1,
(E)-2-[8-(3-chlorophenoxy)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-yli-
dene]propiononitrile (256 mg, 65%) was obtained.
[0168] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.27 (s, 3H), 4.89 (d,
J=12.7 Hz, 1H), 5.04 (s, 2H), 5.50 (d, J=12.7 Hz, 1H), 6.80-7.30
(m, 8H), 7.42-7.56 (m, 3H).
[step 2] Using
(E)-2-[8-(3-chlorophenoxy)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-yliden-
e]propiononitrile (108 mg, 0.278 mmol) obtained in step 1 and in
the same manner as in Example 5, the title compound (compound 22)
(105 mg, 85%) was obtained.
[0169] ESI-MS m/z: 445 (M-H).sup.-; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.30 (s, 3H), 4.93 (d, J=12.7 Hz, 1H), 5.04 (s, 2H), 5.61
(d, J=12.7 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 6.89-7.34 (m, 8H), 7.44
(d, J=7.9 Hz, 1H), 7.52 (s, 1H).
Example 23
(E)-8-(Indazol-1-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)e-
thylidene]-6,11-dihydrodibenzo[b,e]oxepine (Compound 23)
[0170] [step 1] Indazole (240 mg, 2.03 mmol) was dissolved in DMF
(5.0 ml), sodium hydride (60%, 81 mg, 2.03 mmol) was added, and the
mixture was stirred for 15 min. To this mixture was added
(E)-2-(8-chloromethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propionon-
itrile (300 mg, 1.01 mmol) obtained in Reference Example B5, and
the mixture was stirred at room temperature for 3 hr. Ethyl acetate
was added to the mixture, and the organic layer was washed with
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate=90/10 to 75/25) to give
(E)-2-[8-(indazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]p-
ropiononitrile (245 mg, 64%) and
(E)-2-[8-(indazol-2-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]p-
ropiononitrile (138 mg, 36%).
[0171] indazol-1-yl form: .sup.1H-NMR (CDCl.sub.3, .delta.): 2.23
(s, 3H), 4.76 (d, J=12.5 Hz, 1H), 5.40 (d, J=12.5 Hz, 1H), 5.60 (s,
2H), 6.80-7.83 (m, 10H), 8.06 (s, 1H), 8.09 (brs, 1H).
[0172] indazol-2-yl form: .sup.1H-NMR (CDCl.sub.3, .delta.): 2.25
(s, 3H), 4.80 (d, J=12.9 Hz, 1H), 5.44 (d, J=12.9 Hz, 1H), 5.62 (s,
2H), 6.80-7.40 (m, 8H), 7.48 (d, J=7.9 Hz, 1H), 7.64 (dd, J=1.0,
7.6 Hz, 1), 7.73 (dd, J=1.0, 8.6 Hz, 1H), 7.92 (s, 1H).
[step 2] Using
(E)-2-[8-(indazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]p-
ropiononitrile (170 mg, 0.45 mmol) obtained in step 1 and in the
same manner as in Example 5, the title compound (compound 23) (138
mg, 70%) was obtained.
[0173] ESI-MS m/z: 437 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.28 (s, 3H), 4.79 (d, J=12.8 Hz, 1H), 5.53 (s, 2H), 5.58
(d, J=12.8 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.91 (t, J=7.2 Hz, 1H),
7.02-7.50 (m, 8H), 7.76 (d, J=7.9 Hz, 1H), 8.04 (s, 1H).
Example 24
(E)-8-(Indazol-2-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)e-
thylidene]-6,11-dihydrodibenzo[b,e]oxepine (Compound 24)
[0174] Using
(E)-2-[8-(indazol-2-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]p-
ropiononitrile (130 mg, 0.344 mmol) obtained in Example 23, step 1
and in the same manner as in Example 5, the title compound
(compound 24) (101 mg, 67%) was obtained.
[0175] ESI-MS m/z: 437 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.29 (s, 3H), 4.80 (d, J=12.8 Hz, 1H), 5.54 (d, J=12.8
Hz, 1H), 5.57 (s, 2H), 6.83 (d, J=8.2 Hz, 1H), 6.92 (t, J=7.3 Hz,
1H), 7.05-7.40 (m, 7H), 7.60-7.73 (m, 2H), 7.99 (s, 1H).
Example 25
(E)-8-(Benzimidazol-1-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-
-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine.1/2citrate
(Compound 25)
[0176] [step 1]
(E)-2-(8-Hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propiono-
nitrile (500 mg, 1.80 mmol) obtained in Reference Example B4 was
dissolved in THF (19 mL), 2,6-lutidine (1.26 mL, 10.8 mmol),
lithium bromide (0.940 g, 10.8 mmol) and methanesulfonic anhydride
(0.785 g, 4.51 mmol) were added, and the mixture was stirred at
room temperature for 16 hr. Ethyl acetate was added to the mixture,
and the organic layer was washed with brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure to give
a residue.
[0177] Benzimidazole (234 mg, 1.98 mmol) was dissolved in DMF (2.8
ml), potassium carbonate (1.25 g, 9.02 mmol) was added, and the
mixture was stirred for 15 min. To this mixture was added a
solution of the residue obtained above in DMF (7 mL), and the
mixture was stirred at room temperature for 2 hr. Ethyl acetate was
added to the mixture, and the organic layer was washed with brine,
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=7/3 to 5/5) to give
(E)-2-[8-(benzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylid-
ene]propiononitrile (549 mg, 81%).
[0178] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.25 (s, 3H), 4.76 (d,
J=12.8 Hz, 1H), 5.39 (s, 2H), 5.42 (d, J=12.8 Hz, 1H), 6.80-7.35
(m, 9H), 7.47 (d, J=7.9 Hz, 1H), 7.84 (m, 1H), 7.96 (s, 1H).
[step 2] Using
(E)-2-[8-(benzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylid-
ene]propiononitrile (294 mg, 0.779 mmol) obtained in step 1 and in
the same manner as in Example 5, the title compound (compound 25)
(131 mg, 39%) was obtained.
[0179] ESI-MS m/z: 437 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 2.15 (s, 3H), 2.63 (d, J=15.3 Hz, 0.5.times.2H), 2.74 (d,
J=15.3 Hz, 0.5.times.2H), 4.88 (d, J=12.2 Hz, 1H), 5.46 (d, J=12.2
Hz, 1H), 5.48 (s, 2H), 6.77 (dd, J=1.3, 8.2 Hz, 1H), 6.91 (t, J=6.9
Hz, 1H), 7.05 (d, J=7.9 Hz, 1H), 7.10-7.38 (m, 5H), 7.36 (s, 1H),
7.46 (m, 1H), 7.64 (m, 1H), 8.38 (s, 1H).
Example 26
(E)-8-(2-Ethylbenzimidazol-1-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxad-
iazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine (Compound
26)
[0180] [step 1] 2-Ethylbenzimidazole (163 mg, 1.12 mmol) was
dissolved in DMF (5.0 mL), potassium carbonate (0.700 g, 5.07 mmol)
was added, and the mixture was stirred for 15 min. To this mixture
was added
(E)-2-(8-chloromethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propionon-
itrile (300 mg, 1.01 mmol) obtained in Reference Example B5, and
the mixture was stirred at 60.degree. C. for 3 hr. Ethyl acetate
was added to the mixture, and the organic layer was washed with
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate=9/1 to 5/5) to give
(E)-2-[8-(2-ethylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin--
11-ylidene]propiononitrile (318 mg, 70%).
[0181] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.43 (t, J=7.6 Hz, 3H),
2.25 (s, 3H), 2.84 (q, J=7.6 Hz, 2H), 4.73 (d, J=12.6 Hz, 1H), 5.35
(s, 2H), 5.41 (d, J=12.6 Hz, 1H), 6.85 (dd, J=1.0, 8.3 Hz, 1H),
6.86-7.34 (m, 8H), 7.44 (d, J=7.9 Hz, 1H), 7.78 (d, J=6.9 Hz,
1H).
[step 2] Using
(E)-2-[8-(2-ethylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin--
11-ylidene]propiononitrile (157 mg, 0.387 mmol) obtained in step 1
and in the same manner as in Example 5, the title compound
(compound 26) (9 mg, 5%) was obtained.
[0182] ESI-MS m/z: 465 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.30 (t, J=7.6 Hz, 3H), 2.29 (s, 3H), 2.89 (q, J=7.6 Hz,
2H), 4.68 (d, J=12.8 Hz, 1H), 5.37 (s, 2H), 5.54 (d, J=12.8 Hz,
1H), 6.80-7.38 (m, 9H), 6.83 (dd, J=1.1, 7.3 Hz, 1H), 7.76 (m,
1H).
Example 27
(E)-8-(2-Propylbenzimidazol-1-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxa-
diazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine (Compound
27)
[0183] [step 1] Using 2-propylbenzimidazole (179 mg, 1.12 mmol)
instead of 2-ethylbenzimidazole, and in the same manner as in
Example 26, step 1,
(E)-2-[8-(2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-
-11-ylidene]propiononitrile (448 mg, 95%) was obtained.
[0184] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.01 (t, J=7.6 Hz, 3H),
1.90 (m, 2H), 2.25 (s, 3H), 2.80 (t, J=7.6 Hz, 2H), 4.72 (d, J=12.7
Hz, 1H), 5.36 (s, 2H), 5.40 (d, J=12.7 Hz, 1H), 6.84 (d, J=8.6 Hz,
1H), 6.91 (d, J=7.6 Hz, 1H), 6.96 (s, 1H), 7.00-7.33 (m, 6H), 7.44
(d, J=7.6 Hz, 1H), 7.77 (d, J=7.9 Hz, 1H).
[step 2] Using
(E)-2-[8-(2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-
-11-ylidene]propiononitrile (344 mg, 0.82 mmol) obtained in step 1
and in the same manner as in Example 5, the title compound
(compound 27) (46 mg, 12%) was obtained.
[0185] ESI-MS m/z: 479 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.00 (t, J=7.6 Hz, 3H), 1.86 (q, J=7.6 Hz, 2H), 2.29 (s,
3H), 2.79 (t, J=7.6 Hz, 2H), 4.71 (d, J=12.9 Hz, 1H), 5.35 (s, 2H),
5.49 (d, J=12.9 Hz, 1H), 6.82 (dd, J=1.0, 8.3 Hz, 1H), 6.92 (t,
J=7.4 Hz, 1H), 7.00 (s, 1H), 7.04-7.30 (m, 7H), 7.74 (dd, J=2.2,
6.4 Hz, 1H).
Example 28
(E)-8-(2-Isopropylbenzimidazol-1-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4--
oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine
(Compound 28)
[0186] [step 1] Using 2-isopropylbenzimidazole (596 mg, 3.72 mmol)
instead of 2-ethylbenzimidazole, and in the same manner as in
Example 26, step 1,
(E)-2-[8-(2-isopropylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxe-
pin-11-ylidene]propiononitrile (1.246 g, 80%) was obtained.
[0187] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.39 (t, J=7.3 Hz, 6H),
2.24 (s, 3H), 3.12 (m, 2H), 4.72 (d, J=12.8 Hz, 1H), 5.38 (s, 2H),
5.40 (d, J=12.8 Hz, 1H), 6.85 (dd, J=1.1, 8.4 Hz, 1H), 6.88-7.32
(m, 8H), 7.43 (d, J=7.9 Hz, 1H), 7.79 (d, J=7.3 Hz, 1H).
[step 2] Using
(E)-2-[8-(2-isopropylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxe-
pin-11-ylidene]propiononitrile (400 mg, 0.953 mmol) obtained in
step 1 and in the same manner as in Example 5, the title compound
(compound 28) (70 mg, 15%) was obtained.
[0188] ESI-MS m/z: 479 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.37 (d, J=4.8 Hz, 3H), 1.40 (d, J=4.8 Hz, 3H), 2.29 (s,
3H), 3.12 (m, 1H), 4.74 (d, J=12.8 Hz, 1H), 5.39 (s, 2H), 5.51 (d,
J=12.8 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 6.93 (t, J=7.6 Hz, 1H),
7.00-7.30 (m, 8H), 7.77 (dd, J=1.6, 6.9 Hz, 1H).
Example 29
(E)-8-(2-tert-Butylbenzimidazol-1-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-
-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine
(Compound 29)
[0189] [step 1] Using 2-tert-butylbenzimidazole (195 mg, 1.12 mmol)
instead of 2-ethylbenzimidazole, and in the same manner as in
Example 26, step 1,
(E)-2-[8-(2-tert-butylbenzimidazol-1-yl)methyl-6,11-dihydrodibenz-
o[b,e]oxepin-11-ylidene]propiononitrile (89 mg, 18%) was
obtained.
[0190] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.51 (s, 9H), 2.25 (s,
3H), 4.70 (d, J=12.5 Hz, 1H), 5.40 (d, J=12.5 Hz, 1H), 5.62 (s,
2H), 6.85 (dd, J=1.3, 8.1 Hz, 1H), 6.87-7.35 (m, 8H), 7.43 (d,
J=7.9 Hz, 1H), 7.81 (d, J=7.9 Hz, 1H).
[step 2] Using
(E)-2-[8-(2-tert-butylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]ox-
epin-11-ylidene]propiononitrile (86 mg, 0.197 mmol) obtained in
step 1 and in the same manner as in Example 5, the title compound
(compound 29) (61 mg, 63%) was obtained.
[0191] ESI-MS m/z: 493 (M+H).sup.+; .sup.1H-NMR(CDCl.sub.3,
.delta.): 1.50 (s, 9H), 2.27 (s, 3H), 4.73 (d, J=12.9 Hz, 1H), 5.55
(d, J=12.9 Hz, 1H), 5.62 (s, 2H), 6.80-7.30 (m, 10H), 7.78 (d,
J=7.9 Hz, 1H).
Example 30
(E)-8-(2-Methoxymethylbenzimidazol-1-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,-
2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine
(Compound 30)
[0192] [step 1] Using 2-methoxymethylbenzimidazole (100 mg, 0.617
mmol) instead of 2-ethylbenzimidazole, and in the same manner as in
Example 26, step 1,
(E)-2-[8-(2-methoxymethylbenzimidazol-1-yl)methyl-6,11-dihydrodib-
enzo[b,e]oxepin-11-ylidene]propiononitrile (176 mg, 68%) was
obtained.
[0193] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.24 (s, 3H), 3.36 (s,
3H), 4.70 (s, 2H), 4.73 (d, J=12.9 Hz, 1H), 5.41 (d, J=12.5 Hz,
1H), 5.50 (s, 2H), 6.84 (d, J=7.9 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H),
7.00-7.10 (m, 2H), 7.15-7.35 (m, 5H), 7.43 (d, J=7.9 Hz, 1H), 7.81
(m, 1H).
[step 2] Using
(E)-2-[8-(2-methoxymethylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e-
]oxepin-11-ylidene]propiononitrile (123 mg, 0.292 mmol) obtained in
step 1 and in the same manner as in Example 5, the title compound
(compound 30) (45 mg, 32%) was obtained.
[0194] ESI-MS m/z: 481 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.29 (s, 3H), 3.35 (s, 3H), 4.68 (s, 2H), 4.73 (d, J=12.9
Hz, 1H), 5.42-5.56 (m, 3H), 6.82 (d, J=7.3 Hz, 1H), 6.92 (t, J=7.0
Hz, 1H), 7.08-7.35 (m, 8H), 7.78 (m, 1H).
Example 31
(E)-8-(2-Hydroxymethylbenzimidazol-1-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,-
2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine
(Compound 31)
[0195] [step 1] Using 2-hydroxymethylbenzimidazole (276 mg, 1.86
mmol) instead of 2-ethylbenzimidazole, and in the same manner as in
Example 26, step 1,
(E)-2-[8-(2-hydroxymethylbenzimidazol-1-yl)methyl-6,11-dihydrodib-
enzo[b,e]oxepin-11-ylidene]propiononitrile (738 mg, 97%) was
obtained.
[0196] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.23 (s, 3H), 4.72 (d,
J=12.6 Hz, 1H), 4.85 (s, 2H), 5.40 (d, J=12.6 Hz, 1H), 5.44 (s,
2H), 6.84 (d, J=8.3 Hz, 1H), 6.90 (t, J=7.4 Hz, 1H), 7.00-7.39 (m,
7H), 7.43 (d, J=7.9 Hz, 1H), 7.76 (d, J=6.3 Hz, 1H).
[step 2] Using
(E)-2-[8-(2-hydroxymethylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e-
]oxepin-11-ylidene]propiononitrile (600 mg, 1.47 mmol) obtained in
step 1 and in the same manner as in Example 5, the title compound
(compound 31) (279 mg, 41%) was obtained.
[0197] ESI-MS m/z: 467 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.15 (s, 3H), 4.70 (d, J=5.8 Hz, 2H), 4.84 (d, J=12.6 Hz,
1H), 5.46 (d, J=12.6 Hz, 1H), 5.54 (s, 2H), 6.77 (d, J=7.3 Hz, 1H),
6.91 (m, 1H), 7.04 (d, J=7.8 Hz, 1H), 7.09-7.39 (m, 7H), 7.60 (m,
1H).
Example 32
(E)-8-[2-(2-Hydroxyethyl)benzimidazol-1-yl]methyl-11-[1-(5-oxo-4,5-dihydro-
-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine
(Compound 32)
[0198] [step 1] Using 2-(2-hydroxyethyl)benzimidazole (603 mg, 3.72
mmol) instead of 2-ethylbenzimidazole, and in the same manner as in
Example 26, step 1,
(E)-2-{8-[2-(2-hydroxyethyl)benzimidazol-1-yl]methyl-6,11-dihydro-
dibenzo[b,e]oxepin-11-ylidene}propiononitrile (1.40 g, 89%) was
obtained.
[0199] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.25 (s, 3H), 2.98 (t,
J=5.3 Hz, 2H), 4.12 (m, 2H), 4.27 (m, 1H), 4.73 (d, J=12.5 Hz, 1H),
5.35 (s, 2H), 5.41 (d, J=12.5 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.91
(t, J=7.7 Hz, 1H), 6.99 (s, 1H), 7.04 (s, 1H), 7.05 (dd, 3'=1.6,
7.7 Hz, 1H), 7.19-7.38 (m, 4H), 7.44 (d, J=7.9 Hz, 1H), 7.75 (dd,
J=2.3, 6.9 Hz, 1H).
[step 2] Using
(E)-2-{8-[2-(2-hydroxyethyl)benzimidazol-1-yl]methyl-6,11-dihydrodibenzo[-
b,e]oxepin-11-ylidene}propiononitrile (700 mg, 1.66 mmol) obtained
in step 1 and in the same manner as in Example 5, the title
compound (compound 32) (287 mg, 36%) was obtained.
[0200] ESI-MS m/z: 481 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 2.15 (s, 3H), 3.13 (t, J=6.3 Hz, 2H), 3.85 (t, J=6.3 Hz,
2H), 4.86 (d, J=12.6 Hz, 1H), 5.47 (d, J=12.6 Hz, 1H), 5.60 (s,
2H), 6.77 (d, J=7.9 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 7.06 (d, J=7.6
Hz, 1H), 7.10-7.35 (m, 6H), 7.49 (d, J=7.9 Hz, 1H), 7.65 (d, J=7.3
Hz, 1H).
Example 33
(E)-8-(2-Benzylbenzimidazol-1-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxa-
diazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine (Compound
33)
[0201] [step 1] Using 2-benzylbenzimidazole (116 mg, 0.557 mmol)
instead of 2-ethylbenzimidazole, and in the same manner as in
Example 26, step 1,
(E)-2-[8-(2-benzylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-
-11-ylidene]propiononitrile (214 mg, 82%) was obtained.
[0202] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.24 (s, 3H), 4.26 (s,
2H), 4.59 (d, J=12.6 Hz, 1H), 5.21 (s, 2H), 5.32 (d, J=12.6 Hz,
1H), 6.66 (s, 1H), 6.82-7.42 (m, 14H), 7.82 (d, J=7.6 Hz, 1H).
[step 2] Using
(E)-2-[8-(2-benzylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-
-11-ylidene]propiononitrile (213 mg, 0.457 mmol) obtained in step 1
and in the same manner as in Example 5, the title compound
(compound 33) (99 mg, 41%) was obtained.
[0203] ESI-MS m/z: 527 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.27 (s, 3H), 4.25 (s, 2H), 4.58 (d, J=12.7 Hz, 1H), 5.22
(s, 2H), 5.41 (d, J=12.7 Hz, 1H), 6.67 (s, 1H), 6.84 (d, J=8.2 Hz,
1H), 6.89-7.38 (m, 13H), 7.80 (d, J=7.2 Hz, 1H).
Example 34
(E)-8-(2-Phenylbenzimidazol-1-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxa-
diazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine (Compound
34)
[0204] [step 1] Using 2-phenylbenzimidazole (218 mg, 1.12 mmol)
instead of 2-ethylbenzimidazole, and in the same manner as in
Example 26, step 1,
(E)-2-[8-(2-phenylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-
-11-ylidene]propiononitrile (537 mg) was obtained
quantitatively.
[0205] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.26 (s, 3H), 4.74 (d,
J=12.9 Hz, 1H), 5.44 (d, J=12.9 Hz, 1H), 5.47 (s, 2H), 6.87 (dd,
J=1.0, 7.3 Hz, 1H), 6.94 (d, J=6.9 Hz, 1H), 7.06 (s, 1H), 7.07 (d,
J=7.6 Hz, 1H), 7.16-7.72 (m, 11H), 7.88 (d, J=7.6 Hz, 1H).
[step 2] Using
(E)-2-[8-(2-phenylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-
-11-ylidene]propiononitrile (230 mg, 0.507 mmol) obtained in step 1
and in the same manner as in Example 5, the title compound
(compound 34) (183 mg, 70%) was obtained.
[0206] ESI-MS m/z: 513 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.23 (s, 3H), 4.68 (d, J=12.7 Hz, 1H), 5.44 (s, 2H), 5.45
(d, J=12.7 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 6.85-7.70 (m, 14H),
7.83 (m, 1H).
Example 35
(E)-8-(2-Propyl-4-methylbenzimidazol-1-yl)methyl-11-[1-(5-oxo-4,5-dihydro--
1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine
(Compound 35)
[0207] [step 1] Using 4-methyl-2-propylbenzimidazole (EP400835;
1.00 g, 5.74 mmol) instead of 2-ethylbenzimidazole, and in the same
manner as in Example 26, step 1,
(E)-2-[8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene]propiononitrile (2.03 g, 82%) was
obtained.
[0208] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.00 (t, J=7.6 Hz, 3H),
1.80 (m, 2H), 2.24 (s, 3H), 2.69 (s, 3H), 2.83 (t, J=7.6 Hz, 2H),
4.72 (d, J=12.9 Hz, 1H), 5.34 (s, 2H), 5.40 (d, J=12.9 Hz, 1H),
6.80-7.32 (m, 9H), 7.43 (d, J=7.9 Hz, 1H).
[step 2] Using
(E)-2-[8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene]propiononitrile (2.03 g, 4.68 mmol) obtained
in step 1 and in the same manner as in Example 5, the title
compound (compound 35) (1.17 g, 51%) was obtained.
[0209] ESI-MS m/z: 493 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.88 (t, J=7.6 Hz, 3H), 1.66 (m, 2H), 2.14 (s, 3H), 2.49
(s, 3H), 2.75 (t, J=7.6 Hz, 2H), 4.85 (d, J=12.6 Hz, 1H), 5.43 (s,
2H), 5.45 (d, J=12.6 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 6.88-7.08 (m,
5H), 7.12-7.28 (m, 4H).
Example 36
(E)-8-(4-Chloro-2-cyclopropylbenzimidazol-1-yl)methyl-11-[1-(5-oxo-4,5-dih-
ydro-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine
(Compound 36)
[0210] [step 1] Using 4-chloro-2-cyclopropylbenzimidazole (764 mg,
3.97 mmol) obtained in Reference Example A1 instead of
benzimidazole, and in the same manner as in Example 25, step 1,
(E)-2-[8-(4-chloro-2-cyclopropylbenzimidazol-1-yl)methyl-6,11-dihydrodibe-
nzo[b,e]oxepin-11-ylidene]propiononitrile (848 mg, 47%) was
obtained.
[0211] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.07 (m, 2H), 1.30 (m,
2H), 1.88 (m, 1H), 2.25 (s, 3H), 4.74 (d, J=12.7 Hz, 1H), 5.41 (d,
J=12.7 Hz, 1H), 5.47 (s, 2H), 6.82-7.33 (m, 9H), 7.45 (d, J=7.9 Hz,
1H).
[step 2] Using
(E)-2-[8-(4-chloro-2-cyclopropylbenzimidazol-1-yl)methyl-6,11-dihydrodibe-
nzo[b,e]oxepin-11-ylidene]propiononitrile (345 mg, 0.763 mmol)
obtained in step 1 and in the same manner as in Example 5, the
title compound (compound 36) (187 mg, 48%) was obtained.
[0212] ESI-MS m/z: 511 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.89-1.15 (m, 4H), 2.15 (s, 3H), 2.21 (m, 1H), 4.88 (d,
J=12.6 Hz, 1H), 5.46 (d, J=12.6 Hz, 1H), 5.60 (s, 2H), 6.77 (d,
J=7.3 Hz, 1H), 6.91 (m, 1H), 7.00-7.38 (m, 7H), 7.42 (d, J=7.9 Hz,
1H).
Example 37
(E)-2-(4-Phenyl-2-propylimidazol-1-yl)methyl-5-(5-oxo-4,5-dihydro-1,2,4-ox-
adiazol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 37)
[0213] [step 1] Using
(E)-2-(2-bromomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)a-
cetonitrile (200 mg, 0.617 mmol) obtained in Reference Example B1
and in the same manner as in Example 20, step 1,
(E)-2-[2-(4-phenyl-2-propylimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[-
a,d]cyclohepten-5-ylidene]acetonitrile (222 mg, 87%) was
obtained.
[0214] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.31 (t, J=7.6 Hz, 3H),
2.69 (q, J=7.6 Hz, 2H), 3.11 (s, 4H), 5.05 (s, 2H), 5.70 (s, 1H),
6.87 (s, 1H), 6.96 (d, J=7.6 Hz, 1H), 7.06 (s, 1H), 7.18-7.47 (m,
8H), 7.73-7.76 (m, 2H).
[step 2] Using
(E)-2-[2-(4-phenyl-2-propylimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[-
a,d]cyclohepten-5-ylidene]acetonitrile (156 mg, 0.375 mmol)
obtained in step 1 and in the same manner as in Example 5, the
title compound (compound 37) (159 mg, 89%) was obtained.
[0215] ESI-MS m/z: 475 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.31 (t, J=7.6 Hz, 3H), 2.68 (q, J=7.6 Hz, 2H), 2.76-3.07
(m, 2H), 3.08-3.44 (m, 2H), 5.06 (s, 2H), 6.83 (s, 1H), 7.02 (d,
J=7.7 Hz, 1H), 7.03-7.14 (m, 2H), 7.15-7.49 (m, 8H), 7.70-7.75 (m,
2H).
Example 38
(E)-2-(2-Ethyl-3-methylindol-1-yl)methyl-5-(1H-tetrazol-5-yl)methylene-10,-
11-dihydro-5H-dibenzo[a,d]cycloheptene (Compound 38)
[0216] [step 1] 2-Ethyl-3-methylindole (196 mg, 1.23 mmol) was
dissolved in DMF (3.2 mL), sodium hydride (60%; 49 mg, 1.23 mmol)
was added, and the mixture was stirred at room temperature for 15
min. To the reaction mixture was added
(E)-2-(2-bromomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)a-
cetonitrile (200 mg, 0.617 mmol) obtained in Reference Example B1,
and the mixture was stirred at room temperature for 2 hr. Water was
added to the mixture, and the mixture was extracted with ethyl
acetate. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=9/1) to give
(E)-[2-(2-ethyl-3-methylindol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cy-
clohepten-5-ylidene]acetonitrile (117 mg, 47%).
[0217] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.10 (t, J=7.6 Hz, 3H),
2.29 (s, 3H), 2.69 (q, J=7.6 Hz, 2H), 2.95-3.11 (m, 4H), 5.26 (s,
2H), 5.65 (s, 1H), 6.73 (d, J=7.9 Hz, 1H), 6.78 (s, 1H), 7.01-7.35
(m, 7H), 7.40 (m, 1H), 7.52 (d, J=5.3 Hz, 1H).
[step 2] Using
(E)-[2-(2-ethyl-3-methylindol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cy-
clohepten-5-ylidene]acetonitrile (50 mg, 0.124 mmol) obtained in
step 1 and in the same manner as in Example 4, the title compound
(compound 38) (37 mg, 68%) was obtained.
[0218] m/z: 446 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3, .delta.):
1.11 (t, J=7.6 Hz, 3H), 2.30 (s, 3H), 2.70 (q, J=7.6 Hz, 2H), 2.86
(m, 2H), 3.27 (m, 2H), 5.27 (s, 2H), 6.74 (s, 1H), 6.82 (d, J=8.2
Hz, 1H), 7.00-7.49 (m, 9H), 7.53 (m, 1H).
Example 39
(E)-2-(2-Ethyl-3-methylindol-1-yl)methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadia-
zol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 39)
[0219] Using
(E)-[2-(2-ethyl-3-methylindol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cy-
clohepten-5-ylidene]acetonitrile (50 mg, 0.124 mmol) obtained in
Example 38, step 1 and in the same manner as in Example 5, the
title compound (compound 39) (37 mg, 65%) was obtained.
[0220] ESI-MS m/z: 462 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.11 (t, J=7.6 Hz, 3H), 2.30 (s, 3H), 2.69 (q, J=7.6 Hz,
2H), 2.86 (m, 2H), 3.20 (m, 2H), 5.26 (s, 2H), 6.47 (s, 1H), 6.73
(s, 1H), 6.78 (d, J=7.9 Hz, 1H), 7.04-7.22 (m, 4H), 7.22-7.48 (m,
4H), 7.55 (m, 1H).
Example 40
(E)-2-(3-Phenoxyphenoxy)methyl-5-(1H-tetrazol-5-yl)methylene-10,11-dihydro-
-5H-dibenzo[a,d]cycloheptene (Compound 40)
[0221] [step 1]
(E)-2-(2-Chloromethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
acetonitrile (200 mg, 0.715 mmol) obtained in Reference Example B2
and 3-phenoxyphenol (146 mg, 0.786 mmol) were dissolved in DMF (3.2
mL), potassium carbonate (494 mg, 3.60 mmol) was added, and the
mixture was stirred at 60.degree. C. for 2 hr. Water was added to
the mixture, and the mixture was extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/ethyl
acetate=80/20) to give
(E)-2-[2-(3-phenoxyphenoxy)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepte-
n-5-ylidene]acetonitrile (348 mg) quantitatively.
[0222] .sup.1H-NMR (CDCl.sub.3, .delta.): 3.03-3.23 (m, 4H), 4.97
(s, 2H), 5.72 (s, 1H), 6.53-6.75 (m, 3H), 6.95-7.40 (m, 12H), 7.45
(dd, J=1.6, 5.6 Hz, 1H).
[step 2] Using
(E)-2-[2-(3-phenoxyphenoxy)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepte-
n-5-ylidene]acetonitrile (133 mg, 0.310 mmol) obtained in step 1
and in the same manner as in Example 4, the title compound
(compound 40) (112 mg, 76%) was obtained.
[0223] ESI-MS m/z: 473 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.78-3.13 (m, 2H), 3.25-3.45 (m, 2H), 4.98 (s, 2H),
6.60-6.75 (m, 3H), 6.95-7.58 (m, 14H).
Example 41
(E)-2-(Naphthalen-2-yloxy)methyl-5-(1H-tetrazol-5-yl)methylene-10,11-dihyd-
ro-5H-dibenzo[a,d]cycloheptene (Compound 41)
[0224] Using 2-naphthol (113 mg, 0.786 mmol) instead of
3-phenoxyphenol, and in the same manner as in Example 40, the title
compound (compound 41) (42 mg, 12%) was obtained.
[0225] ESI-MS m/z: 431 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.79-3.21 (m, 2H), 3.30-3.52 (m, 2H), 5.15 (s, 2H), 7.13
(s, 1H), 7.15-7.52 (m, 10H), 7.54 (d, J=7.9 Hz, 1H), 7.69-7.85 (m,
3H).
Example 42
(E)-2-(2-Ethyl-7-methyl-3H-imidazo[4,5-c]pyridin-3-yl)methyl-5-(1H-tetrazo-
l-5-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 42)
[0226] [step 1] Using 2-ethyl-7-methyl-3H-imidazo[4,5-c]pyridine
(U.S. Pat. No. 5,332,744; 462 mg, 2.87 mmol) instead of
2-propylbenzimidazole, and in the same manner as in Example 1,
(E)-2-[2-(2-ethyl-7-methyl-3H-imidazo[4,5-c]pyridin-3-yl)methyl-10,11-dih-
ydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (408 mg,
35%) was obtained.
[0227] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.41 (t, J=7.6 Hz, 3H),
2.64 (s, 3H), 2.91 (q, J=7.6 Hz, 2H), 3.07 (s, 4H), 5.34 (s, 2H),
5.67 (s, 1H), 6.82-7.46 (m, 7H), 8.23 (s, 1H), 8.40 (s, 1H).
[step 2] Using
(E)-2-[2-(2-ethyl-7-methyl-3H-imidazo[4,5-c]pyridin-3-yl)methyl-10,11-dih-
ydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (70 mg,
0.173 mmol) obtained in step 1 and in the same manner as in Example
4, the title compound (compound 42) (22 mg, 28%) was obtained.
[0228] ESI-MS m/z: 448 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.43 (3H, t, J=7.5 Hz), 2.46-3.10 (4H, m), 2.62 (3H, s),
2.94 (2H, q, J=7.5 Hz), 5.34 (2H, s), 6.68 (1H, s), 6.93-7.17 (6H,
m), 7.46 (1H, d, J=8.1 Hz), 7.90 (1H, s), 8.27 (1H, s).
Example 43
(E)-[2-(Biphenyl-3-ylaminomethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-
-5-ylidene]acetonitrile (Compound 43)
[0229] Using 3-aminobiphenyl (1.20 g, 7.09 mmol) instead of
2-propylbenzimidazole, and in the same manner as in Example 1, the
title compound (compound 43) (680 mg, 46%) was obtained.
[0230] ESI-MS m/z: 413 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 3.05-3.22 (m, 4H), 4.35 (s, 2H), 5.71 (s, 1H), 6.56-6.60
(m, 1H), 6.80-6.83 (m, 1H), 6.95 (d, J=7.6 Hz, 1H), 7.16-7.28 (m,
5H), 7.29-7.47 (m, 6H), 7.51-7.54 (m, 2H).
Example 44
(E)-[2-(N-(Biphenyl-3-yl)-2-carboxyacetamido)methyl-10,11-dihydro-5H-diben-
zo[a,d]cyclohepten-5-ylidene]acetonitrile (Compound 44)
[0231] [step 1] Compound 43 (200 mg, 0.49 mmol) obtained in Example
43 was dissolved in DMF (1 mL), and the mixture was cooled to
0.degree. C. Methyl 3-chloro-3-oxopropanoate (99 mg, 0.73 mmol) was
added, and the mixture was stirred at room temperature for 7 hr. To
this mixture was added saturated aqueous sodium hydrogen carbonate
solution (20 mL), and the precipitate was collected by filtration
to give
(E)-[2-(N-(biphenyl-3-yl)-3-methoxy-3-oxopropanamido)methyl-10,11-dihydro-
-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile
quantitatively.
[0232] ESI-MS m/z: 513 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 3.11 (br, 4H), 3.28 (s, 2H), 3.66 (s, 3H), 4.90 (s, 2H),
5.69 (s, 1H), 7.01 (d, J=7.6 Hz, 1H), 7.06 (s, 1H), 7.08-7.18 (m,
2H), 7.19-7.25 (m, 2H), 7.28-7.47 (m, 9H), 7.55 (d, J=7.6 Hz,
1H).
[step 2]
(E)-[2-(N-(Biphenyl-3-yl)-3-methoxy-3-oxopropanamido)methyl-10,1-
1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (52 mg,
0.10 mmol) obtained in step 1 was dissolved in ethanol (2 mL), 2
mol/L aqueous sodium hydroxide solution (0.1 mL) was added, and the
mixture was stirred at room temperature for 3 hr. The mixture was
adjusted to pH 2 with 2 mol/L hydrochloric acid, and the mixture
was extracted with chloroform. The organic layer was washed with
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by reversed-phase
liquid chromatography (water/acetonitrile=7/3 to 1/9) to give the
title compound (compound 44) (30 mg, 60%).
[0233] ESI-MS m/z: 499 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 3.10 (s, 4H), 3.17 (s, 2H), 4.91 (s, 2H), 5.69 (s, 1H),
6.95 (d, J=7.6 Hz, 1H), 7.02 (s, 1H), 7.05-7.08 (m, 1H), 7.21-7.25
(m, 2H), 7.31 (d, J=7.6 Hz, 2H), 7.36 (s, 6H), 7.44-7.51 (m, 2H),
7.60-7.64 (m, 1H).
Example 45
(E)-{2-[(Biphenyl-3-ylbutyrylamino)methyl]-10,11-dihydro-5H-dibenzo[a,d]cy-
clohepten-5-ylidene}acetonitrile (Compound 45)
[0234] Compound 43 (27 mg, 0.066 mmol) obtained in Example 43 was
dissolved in DMF (1 ml), pyridine (6.2 mg, 0.079 mmol) and butyryl
chloride (8.4 mg, 0.079 mmol) were added, and the mixture was
stirred at room temperature for 5 hr. Water and saturated aqueous
sodium hydrogen carbonate solution were added to the mixture, and
the mixture was filtered to give the title compound (compound 45)
(28 mg, 88%).
[0235] ESI-MS m/z: 483 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.) 0.84 (t, J=7.4 Hz, 3H), 1.60-1.66 (m, 2H), 2.10 (t, J=7.6
Hz, 2H), 3.08 (s, 4H), 4.87 (s, 2H), 5.69 (s, 1H), 6.94-7.11 (m,
4H), 7.19-7.24 (m, 2H), 7.31-7.41 (m, 8H), 7.43-7.48 (m, 1H), 7.53
(d, J=7.6 Hz, 1H).
Example 46
(E)-2-[(Biphenyl-3-ylbutyrylamino)methyl]-5-(1H-tetrazol-5-yl)methylene-10-
,11-dihydro-5H-dibenzo[a,d]cycloheptene (Compound 46)
[0236] Using the compound 45 (27 mg, 0.07 mmol) obtained in Example
45 and in the same manner as in Example 4, the title compound
(compound 46) (20 mg, 95%) was obtained.
[0237] ESI-MS m/z: 526 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.) 0.85 (t, J=7.4 Hz, 3H), 1.52-1.72 (m, 2H), 2.11 (t, J=7.4
Hz, 2H), 2.78-3.05 (m, 2H), 3.20-3.43 (m, 2H), 4.87 (d, J=3.3 Hz,
2H), 6.99 (d, J=7.9 Hz, 1H), 7.03 (s, 1H), 7.08 (s, 1H), 7.11 (d,
J=9.6 Hz, 2H), 7.20 (d, J=6.9 Hz, 1H), 7.31-7.47 (m, 10H), 7.55 (d,
J=7.9 Hz, 1H).
Example 47
(E)-[2-(4-Methyl-6-phenyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5-
H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (Compound 47)
[0238] [step 1] Under a nitrogen atmosphere,
6-bromo-4-methyl-2-propylbenzimidazole (WO2004082621; 300 mg, 1.19
mmol) was dissolved in DMF (3 mL), and the mixture was cooled to
0.degree. C. Potassium carbonate (829 mg, 6.00 mmol) was added, and
the mixture was stirred at room temperature for 20 min. To this
mixture was added
(E)-2-(2-bromomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)a-
cetonitrile (421 mg, 1.30 mmol) obtained in Reference Example B1,
and the mixture was stirred at room temperature for 4 hr. Ethyl
acetate was added to the mixture, and the organic layer was washed
with brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/3)
to give
(E)-[2-(6-bromo-4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5-
H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (615 mg, 95%).
[0239] ESI-MS m/z: 496 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.99 (t, J=7.3 Hz, 3H), 1.72-1.88 (m, 2H), 2.64 (s, 3H),
2.78 (t, J=7.3 Hz, 2H), 3.07 (s, 4H), 5.23 (s, 2H), 5.68 (s, 1H),
6.76 (s, 1H), 6.81 (d, J=7.9 Hz, 1H), 7.10 (s, 1H), 7.15-7.37 (m,
5H), 7.44 (d, J=6.8 Hz, 1H).
[step 2] Under a nitrogen atmosphere,
(E)-[2-(6-bromo-4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5-
H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (910 mg, 1.83
mmol) obtained in step 1 was dissolved in DMF (25 mL),
phenylboronic acid (666 mg, 5.46 mmol), cesium carbonate (1.19 g,
3.64 mmol) and tetrakis(triphenylphosphine)palladium (421 mg, 0.36
mmol) were added, and the mixture was stirred at 100.degree. C. for
12 hr. Water was added to the mixture, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate=1/1 too/1) to give the
title compound (compound 47) (703 mg, 87%).
[0240] ESI-MS m/z: 494 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.01 (t, J=7.3 Hz, 3H), 1.72-1.90 (m, 2H), 2.74 (s, 3H),
2.83 (t, J=7.3 Hz, 2H), 3.06 (s, 4H), 5.34 (d, J=9.3 Hz, 2H), 5.66
(s, 1H), 6.82 (s, 1H), 6.86 (d, J=7.9 Hz, 1H), 7.12 (s, 1H),
7.17-7.24 (m, 2H), 7.28-7.44 (m, 7H), 7.54 (d, J=8.4 Hz, 2H).
Example 48
(E)-2-(4-Methyl-6-phenyl-2-propylbenzimidazol-1-yl)methyl-5-(1H-tetrazol-5-
-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (Compound
48)
[0241] Using compound 47 (500 mg, 1.01 mmol) obtained in Example 47
and in the same manner as in Example 4, the title compound
(compound 48) (470 mg, 87%) was obtained.
[0242] ESI-MS m/z: 537 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.00 (t, J=7.4 Hz, 3H), 1.73-1.89 (m, 2H), 2.71 (s, 3H),
2.73-2.98 (br, 2H), 2.84 (t, J=7.4 Hz, 2H), 3.15-3.39 (br, 2H),
5.33 (s, 2H), 6.76 (s, 1H), 6.95 (d, J=7.9 Hz, 1H), 7.04 (s, 1H),
7.17 (d, J=6.9 Hz, 2H), 7.28-7.46 (m, 8H), 7.55 (d, J=5.3 Hz,
2H).
Example 49
(E)-2-(4-Methyl-6-phenyl-2-propylbenzimidazol-1-yl)methyl-5-(5-oxo-4,5-dih-
ydro-1,2,4-oxadiazol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cyclohept-
ene (Compound 49)
[0243] Using compound 47 (50 mg, 0.10 mmol) obtained in Example 47
and in the same manner as in Example 5, the title compound
(compound 49) (15 mg, 28%) was obtained.
[0244] ESI-MS m/z: 553 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.03 (t, J=7.3 Hz, 3H), 1.78-1.93 (m, 2H), 2.72-3.01 (m,
2H), 2.77 (s, 3H), 3.14-3.45 (m, 2H), 3.22 (t, J=7.9 Hz, 2H), 5.46
(s, 2H), 6.50 (s, 1H), 6.79 (s, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.17
(d, J=6.6 Hz, 1H), 7.27-7.52 (m, 11H).
Example 50
(E)-[2-(2-Ethyl-4-methyl-6-phenylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-
-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (Compound 50)
[0245] [step 1] Using 6-bromo-2-ethyl-4-methylbenzimidazole
(WO2004082621; 500 mg, 2.09 mmol) and in the same manner as in
Example 47, step 1,
(E)-[2-(6-bromo-2-ethyl-4-methylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-
-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (900 mg, 89%) was
obtained.
[0246] ESI-MS m/z: 482 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.36 (t, J=7.5 Hz, 3H), 2.65 (s, 3H), 2.83 (q, J=7.5 Hz,
2H), 3.07 (s, 4H), 5.23 (s, 2H), 5.68 (s, 1H), 6.76 (s, 1H), 6.82
(d, J=8.1 Hz, 1H), 7.11 (s, 1H), 7.17-7.35 (m, 5H), 7.43 (d, J=7.7
Hz, 1H).
[step 2] Using
(E)-[2-(6-bromo-2-ethyl-4-methylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-
-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (200 mg, 0.41 mmol)
obtained in step 1 and in the same manner as in Example 47, step 2,
the title compound (compound 50) (183 mg, 93%) was obtained.
[0247] ESI-MS m/z: 480 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.37 (t, J=7.5 Hz, 3H), 2.74 (s, 3H), 2.88 (q, J=7.5 Hz,
2H), 3.06 (s, 4H), 5.33 (s, 2H), 5.66 (s, 1H), 6.83 (s, 1H), 6.87
(d, J=7.7 Hz, 1H), 7.14 (s, 1H), 7.18-7.33 (m, 5H), 7.35-7.45 (m,
4H), 7.55 (d, J=7.6 Hz, 2H).
Example 51
(E)-2-(2-Ethyl-4-methyl-6-phenylbenzimidazol-1-yl)methyl-5-(1H-tetrazol-5--
yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (Compound
51)
[0248] Using compound 50 (100 mg, 0.21 mmol) obtained in Example 50
and in the same manner as in Example 4, the title compound
(compound 51) (91 mg, 83%) was obtained.
[0249] ESI-MS m/z: 523 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.36 (t, J=7.6 Hz, 3H), 2.70 (s, 3H), 2.72-2.98 (br, 2H),
2.88 (q, J=7.6 Hz, 2H), 3.12-3.40 (br, 2H), 5.33 (s, 2H), 6.76 (s,
1H), 6.95 (d, J=7.9 Hz, 1H), 7.04 (s, 1H), 7.16 (d, J=6.9 Hz, 2H),
7.27-7.45 (m, 8H), 7.55 (d, J=7.3 Hz, 2H).
Example 52
(E)-2-(2-Ethyl-4-methyl-6-phenylbenzimidazol-1-yl)methyl-5-(5-oxo-4,5-dihy-
dro-1,2,4-oxadiazol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cyclohepte-
ne (Compound 52)
[0250] Using compound 50 (43 mg, 0.09 mmol) obtained in step 50 and
in the same manner as in Example 5, the title compound (compound
52) (16 mg, 33%) was obtained.
[0251] ESI-MS m/z: 539 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): .sup.1H-NMR (CDCl.sub.3) .delta.: 1.38 (t, J=7.5 Hz, 3H),
2.74 (s, 3H), 2.75-2.97 (m, 2H), 2.88 (q, J=7.5 Hz, 2H), 3.16-3.42
(m, 2H), 5.32 (s, 2H), 6.48 (s, 1H), 6.76 (s, 1H), 6.92 (d, J=6.6
Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.28-7.51 (m, 6H), 7.52-7.58 (m,
2H), 7.63-7.71 (m, 2H).
Example 53
(E)-[2-(2,4-Dimethyl-6-phenylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dib-
enzo[a,d]cyclohepten-5-ylidene]acetonitrile (Compound 53)
[0252] Using 2,4-dimethyl-6-phenylbenzimddazole (137 mg, 0.62 mmol)
obtained in Reference Example A4 and in the same manner as in
Example 47, step 1, the title compound (compound 53) (223 mg, 77%)
was obtained.
[0253] ESI-MS m/z: 466 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.57 (s, 3H), 2.73 (s, 3H), 3.06 (s, 4H), 5.31 (s, 2H),
5.66 (s, 1H), 6.83 (s, 1H), 6.89 (d, J=8.1 Hz, 1H), 7.17-7.24 (m,
3H), 7.28-7.34 (m, 4H), 7.37-7.44 (m, 3H), 7.56 (d, J=7.7 Hz,
2H).
Example 54
(E)-2-(2,4-Methyl-6-phenylbenzimidazol-1-yl)methyl-5-(1H-tetrazol-5-yl)met-
hylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (Compound 54)
[0254] Using compound 53 (100 mg, 0.21 mmol) obtained in Example 53
and in the same manner as in Example 4, the title compound
(compound 54) (80 mg, 74%) was obtained.
[0255] ESI-MS m/z: 509 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.57 (s, 3H), 2.67 (s, 3H), 2.71-2.97 (m, 2H), 3.10-3.37
(m, 2H), 5.31 (s, 2H), 6.76 (s, 1H), 6.97 (d, J=7.0 Hz, 1H), 7.03
(s, 1H), 7.14 (d, J=7.3 Hz, 1H), 7.19-7.45 (m, 9H), 7.56 (d, J=7.3
Hz, 2H).
Example 55
(E)-[2-(2,4-Dimethyl-6-phenylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dib-
enzo[a,d]cyclohepten-5-ylidene]acetic acid (Compound 55)
[0256] Compound 53 (80 mg, 0.17 mmol) obtained in Example 53 was
suspended in ethanol (2 mL), 10 mol/L aqueous sodium hydroxide
solution (3.1 mL) was added, and the mixture was stirred under
reflux for 3 days. Under ice-cooling, the mixture was adjusted to
pH 1 with 2 mol/L hydrochloric acid, and the mixture was extracted
with ethyl acetate. The organic layer was washed with brine, dried
over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (chloroform/methanol=98/2 to 90/10) to give the
title compound (compound 55) (34 mg, 41%).
[0257] ESI-MS m/z: 485 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.73 (s, 3H), 2.80 (s, 3H), 2.93-3.46 (m, 4H), 5.36 (s,
2H), 6.17 (s, 1H), 6.79 (s, 1H), 6.90 (d, J=7.9 Hz, 1H), 7.12-7.24
(m, 5H), 7.28-7.47 (m, 5H), 7.52 (d, J=8.3 Hz, 2H).
Example 56
(E)-[2-(2,4-Dimethyl-6-phenylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dib-
enzo[a,d]cyclohepten-5-ylidene]acetamide (Compound 56)
[0258] Using compound 53 (80 mg, 0.17 mmol) obtained in Example 53
and in the same manner as in Example 3, the title compound
(compound 56) (12 mg, 15%) was obtained.
[0259] ESI-MS m/z: 484 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.) 2.85 (s, 3H), 3.03 (s, 3H), 5.37 (br s, 8H), 6.21 (s, 1H),
6.73 (s, 1H), 6.98 (s, 1H), 7.22 (d, J=7.6 Hz, 3H), 7.31-7.50 (m,
9H).
Example 57
N-{(E)-[2-(2,4-Dimethyl-6-phenylbenzimidazol-1-yl)methyl-10,11-dihydro-5H--
dibenzo[a,d]cyclohepten-5-ylidene]acetyl}methanesulfonamide
(Compound 57)
[0260]
(E)-[2-(2,4-Dimethyl-6-phenylbenzimidazol-1-yl)methyl-10,11-dihydro-
-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetic acid (50 mg, 0.10
mmol) obtained in Example 55 was dissolved in DMF (2 mL), and the
mixture was cooled to 0.degree. C. N,N'-carbonyldiimidazole (36 mg,
0.22 mmol) was added, and the mixture was stirred at room
temperature for 2 hr. To this mixture were added methanesulfonamide
(21 mg, 0.22 mmol) and DBU (21 mg, 0.22 mmol), and the mixture was
stirred at 60.degree. C. for 5 hr. 5% Aqueous citric acid solution
was added to the mixture, and the precipitate was collected by
filtration, and washed with water to give the title compound
(compound 57) (31 mg, 55%).
[0261] ESI-MS m/z: 562 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.) 2.57 (s, 3H), 2.82-3.23 (m, 4H), 3.16 (s, 3H), 3.32 (s,
3H), 5.49 (s, 2H), 6.27 (s, 1H), 6.91 (d, J=7.6 Hz, 1H), 6.99 (s,
1H), 7.03-7.15 (m, 2H), 7.18-7.35 (m, 5H), 7.42 (t, J=7.6 Hz, 2H),
7.57 (s, 1H), 7.64 (d, J=8.3 Hz, 2H).
Example 58
(E)-2-(2-Hydroxymethyl-4-methyl-6-phenylbenzimidazol-1-yl)methyl-5-(5-oxo--
4,5-dihydro-1,2,4-oxadiazol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cy-
cloheptene (Compound 58)
[0262] [step 1] Using
2-hydroxymethyl-4-methyl-6-phenylbenzimidazole (200 mg, 0.84 mmol)
obtained in Reference Example A6 and in the same manner as in
Example 47, step 1,
(E)-[2-(2-hydroxymethyl-4-methyl-6-phenylbenzimidazol-1-yl)methyl-10,11-d-
ihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (301 mg,
75%) was obtained.
[0263] ESI-MS m/z: 482 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.72 (s, 3H), 3.06 (s, 4H), 4.87 (d, J=5.5 Hz, 2H), 5.44
(s, 2H), 5.65 (s, 1H), 6.86-6.95 (m, 2H), 7.17-7.23 (m, 3H),
7.27-7.35 (m, 4H), 7.37-7.44 (m, 3H), 7.52-7.57 (m, 2H).
[step 2] Using
(E)-[2-(2-hydroxymethyl-4-methyl-6-phenylbenzimidazol-1-yl)methyl-10,11-d-
ihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (100 mg,
0.21 mmol) obtained in step 1 and in the same manner as in Example
5, the title compound (compound 58) (42 mg, 39%) was obtained.
[0264] ESI-MS m/z: 541 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.71 (s, 3H), 2.76-2.97 (m, 2H), 3.16-3.40 (m, 2H), 4.88
(s, 2H), 5.43 (s, 2H), 6.45 (s, 1H), 6.84 (s, 1H), 6.93 (d, J=8.3
Hz, 1H), 7.13 (d, J=7.3 Hz, 1H), 7.20 (s, 1H), 7.28-7.34 (m, 5H),
7.37-7.43 (m, 3H), 7.52-7.56 (m, 2H).
Example 59
(E)-2-[2-(2-Hydroxyethyl)-4-methyl-6-phenylbenzimidazol-1-yl]methyl-5-(5-o-
xo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d-
]cycloheptene (Compound 59)
[0265] [step 1] Using
2-(2-hydroxyethyl)-4-methyl-6-phenylbenzimidazole (157 mg, 0.62
mmol) obtained in Reference Example A5 and in the same manner as in
Example 47, step 1,
(E)-{2-[2-(2-hydroxyethyl)-4-methyl-6-phenylbenzimidazol-1-yl]methyl-10,1-
1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (278
mg, 91%) was obtained.
[0266] ESI-MS m/z: 496 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.70 (s, 3H), 2.96 (t, J=5.3 Hz, 2H), 3.06 (s, 4H), 4.12
(t, J=5.3 Hz, 2H), 5.31 (s, 2H), 5.66 (s, 1H), 6.84 (s, 1H), 6.87
(d, (7=7.7 Hz, 1H), 7.18-7.24 (m, 3H), 7.27-7.36 (m, 4H), 7.36-7.45
(m, 3H), 7.56 (d, J=8.0 Hz, 2H).
[step 2] Using
(E)-{2-[2-(2-hydroxyethyl)-4-methyl-6-phenylbenzimidazol-1-yl]methyl-10,1-
1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (100
mg, 0.20 mmol) obtained in step 1 and in the same manner as in
Example 5, the title compound (compound 59) (24 mg, 22%) was
obtained.
[0267] ESI-MS m/Z: 555 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.70 (s, 3H), 2.81-2.89 (br, 2H), 2.96 (t, J=5.5 Hz, 2H),
3.26-3.32 (br, 2H), 4.12 (t, J=5.5 Hz, 2H), 5.31 (s, 2H), 6.48 (s,
1H), 6.78 (s, 1H), 6.93 (d, J=7.9 Hz, 1H), 7.15 (d, J=7.3 Hz, 1H),
7.21 (s, 1H), 7.27-7.36 (m, 5H), 7.40 (t, J=7.3 Hz, 3H), 7.56 (d,
J=7.9 Hz, 2H).
Example 60
(E)-2-(6-Phenyl-4-methylbenzimidazol-1-yl)methyl-5-(1H-tetrazol-5-yl)methy-
lene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (Compound 60)
[0268] [step 1]
(E)-{2-[2-(2-Hydroxyethyl)-4-methyl-6-phenylbenzimidazol-1-yl]methyl-10,1-
1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (100
mg, 0.20 mmol) obtained in Example 59, step 1 was dissolved in
acetonitrile (2 mL),
1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (128 mg,
0.30 mmol) was added, and the mixture was stirred at room
temperature for 4 hr. Chloroform (20 mL) and saturated aqueous
sodium hydrogen carbonate solution (20 mL) were added to the
mixture, and the mixture was stirred at room temperature for 30
min. The organic layer was washed with brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(chloroform/methanol=100/0 to 95/15) to give
(E)-[2-(4-methyl-6-phenylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenz-
o[a,d]cyclohepten-5-ylidene]acetonitrile (14 mg, 15%).
[0269] ESI-MS m/z: 452 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 2.62 (s, 3H), 2.97-3.14 (m, 4H), 5.66 (s, 2H), 6.15 (s,
1H), 7.24-7.42 (m, 8H), 7.48 (t, J=7.4 Hz, 2H), 7.57 (s, 1H), 7.69
(d, J=7.4 Hz, 2H), 7.88 (s, 1H), 9.22 (s, 1H).
[step 2] Using
(E)-[2-(4-methyl-6-phenylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenz-
o[a,d]cyclohepten-5-ylidene]acetonitrile (10 mg, 0.02 mmol)
obtained in step 1 and in the same manner as in Example 4, the
title compound (compound 60) (3.4 mg, 34%) was obtained.
[0270] ESI-MS m/z: 495 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.73 (s, 3H), 2.76-3.03 (m, 2H), 3.17-3.40 (m, 2H), 5.35
(s, 2H), 6.90 (s, 1H), 7.07 (s, 1H), 7.10 (d, J=7.9 Hz, 1H), 7.18
(d, J=6.9 Hz, 1H), 7.28-7.34 (m, 3H), 7.39-7.48 (m, 6H), 7.56 (d,
J=7.9 Hz, 2H), 7.94 (s, 1H).
Example 61
(E)-2-[2-(2-Methoxycarbonylethyl)-4-methyl-6-phenylbenzimidazol-1-yl]methy-
l-5-(1H-tetrazol-5-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 61)
[0271] [step 1] Using
2-(2-methoxycarbonylethyl)-4-methyl-6-phenylbenzimidazole (400 mg,
1.36 mmol) obtained in Reference Example A7 and in the same manner
as in Example 47, step 1,
(E)-{2-[2-(2-methoxycarbonylethyl)-4-methyl-6-phenylbenzimidazol-1-yl]met-
hyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(590 mg, 81%) was obtained.
[0272] ESI-MS m/z: 538 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.71 (s, 3H), 2.97 (t, J=7.3 Hz, 2H), 3.06-3.13 (m, 6H),
3.66 (s, 3H), 5.39 (s, 2H), 5.66 (s, 1H), 6.86 (s, 2H), 6.89 (d,
J=7.9 Hz, 2H), 7.18-7.23 (m, 3H), 7.28-7.33 (m, 3H), 7.35-7.45 (m,
2H), 7.55 (d, J=7.9 Hz, 2H).
[step 2] Using
(E)-{2-[2-(2-methoxycarbonylethyl)-4-methyl-6-phenylbenzimidazol-1-yl]met-
hyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(100 mg, 0.19 mmol) obtained in step 1 and in the same manner as in
Example 4, the title compound (compound 61) (23 mg, 21%) was
obtained.
[0273] ESI-MS m/z: 581 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 2.63 (s, 3H), 2.95 (t, J=7.1 Hz, 2H), 3.31 (t, J=7.1 Hz,
2H), 3.58 (s, 3H), 3.74-4.52 (m, 4H), 5.74 (s, 2H), 6.81 (s, 1H),
6.87 (d, J=7.6 Hz, 1H), 6.98-7.10 (m, 2H), 7.13 (s, 1H), 7.17-7.30
(m, 2H), 7.32-7.51 (m, 4H), 7.56 (s, 1H), 7.68 (d, J=7.3 Hz, 2H),
7.83 (s, 1H).
Example 62
(E)-2-[2-(2-Methanesulfonylaminocarbonylethyl)-4-methyl-6-phenylbenzimidaz-
ol-1-yl]methyl-5-(1H-tetrazol-5-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]-
cycloheptene (Compound 62)
[0274] [step 1]
(E)-{2-[2-(2-Methoxycarbonylethyl)-4-methyl-6-phenylbenzimidazol-1-yl]met-
hyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(350 mg, 0.65 mmol) obtained in Example 61, step 1 was dissolved in
ethanol (4 mL), 2 mol/L aqueous sodium hydroxide solution (0.8 mL)
was added, and the mixture was stirred at room temperature for 2
hr. The mixture was concentrated under reduced pressure, water and
2 mol/L hydrochloric acid were added, and the precipitate was
collected by filtration to give
(E)-[2-{2-(2-carboxyethyl)-4-methyl-6-phenylbenzimidazol-1-yl}methyl-10,1-
1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (336
mg, 99%).
[0275] ESI-MS m/z: 524 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.73 (s, 3H), 3.03-3.14 (m, 6H), 3.16-3.24 (m, 2H), 5.43
(s, 2H), 5.67 (s, 1H), 6.86 (s, 1H), 6.89 (d, J=8.8 Hz, 1H),
7.20-7.24 (m, 2H), 7.27-7.46 (m, 8H), 7.53 (d, J=8.1 Hz, 2H).
[step 2] Using
(E)-[2-{2-(2-carboxyethyl)-4-methyl-6-phenylbenzimidazol-1-yl}methyl-10,1-
1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (100
mg, 0.19 mmol) obtained in step 1 and in the same manner as in
Example 57,
(E)-{2-[2-(2-methanesulfonylaminocarbonylethyl)-4-methyl-6-phenylbenzimid-
azol-1-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}aceton-
itrile (114 mg, 100%) was obtained.
[0276] ESI-MS m/z: 601 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.74 (s, 3H), 2.88-2.97 (m, 2H), 3.04-3.14 (m, 6H), 3.27
(s, 3H), 5.32 (s, 2H), 5.67 (s, 1H), 6.84-6.90 (m, 2H), 7.19-7.25
(m, 2H), 7.28-7.46 (m, 8H), 7.57 (d, J=7.6 Hz, 2H).
[step 3] Using
(E)-{2-[2-(2-methanesulfonylaminocarbonylethyl)-4-methyl-6-phenylbenzimid-
azol-1-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}aceton-
itrile (60 mg, 0.10 mmol) obtained in step 2 and in the same manner
as in Example 4, the title compound (compound 62) (33 mg, 52%) was
obtained.
[0277] ESI-MS m/z: 644 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.74 (s, 3H), 2.79-3.02 (m, 2H), 2.91-2.99 (m, 2H),
3.07-3.16 (m, 2H), 3.21-3.41 (m, 2H), 3.27 (s, 3H), 5.32 (s, 2H),
6.79 (s, 1H), 6.97 (d, J=7.7 Hz, 1H), 7.07 (s, 1H), 7.19 (d, J=8.1
Hz, 1H), 7.31-7.47 (m, 9H), 7.57 (d, J=7.0 Hz, 2H).
Example 63
(E)-2-[2-(2-Methylcarbamoylethyl)-4-methyl-6-phenylbenzimidazol-1-yl]methy-
l-5-(1H-tetrazol-5-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 63)
[0278] [step 1]
(E)-{2-[2-(2-Carboxyethyl)-4-methyl-6-phenylbenzimidazol-1-yl]methyl-10,1-
1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (100
mg, 0.19 mmol) obtained in Example 62, step 1 was dissolved in DMF
(1 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (527 mg, 2.75
mmol), 1-hydroxybenzotriazole (421 mg, 2.75 mmol) and methylamine
(2 mol/L THF solution; 0.38 mL, 0.72 mmol) were added, and the
mixture was stirred at room temperature for 24 hr. Saturated
aqueous sodium hydrogen carbonate solution and water were added to
the mixture, and the precipitated solid was collected by filtration
to give
(E)-{2-[2-(methylcarbamoylethyl)-4-methyl-6-phenylbenzimidazol-1-yl]methy-
l-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(102 mg, 100%).
[0279] ESI-MS m/z: 537 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.71 (s, 3H), 2.76 (d, J=4.6 Hz, 3H), 2.82 (t, J=6.9 Hz,
2H), 3.06 (s, 4H), 3.11 (t, J=6.9 Hz, 3H), 5.37 (s, 2H), 5.66 (s,
1H), 6.87 (d, J=7.6 Hz, 2H), 7.17-7.24 (m, 3H), 7.27-7.34 (m, 3H),
7.36-7.44 (m, 3H), 7.56 (d, J=7.9 Hz, 2H).
[step 2] Using
(E)-{2-[2-(methylcarbamoylethyl)-4-methyl-6-phenylbenzimidazol-1-yl]methy-
l-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(50 mg, 0.09 mmol) obtained in step 1 and in the same manner as in
Example 4, the title compound (compound 63) (48 mg, 93%) was
obtained.
[0280] ESI-MS m/z: 580 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.70 (s, 3H), 2.76 (d, J=4.6 Hz, 3H), 2.80-3.00 (m, 2H),
2.81 (t, 0'=6.9 Hz, 2H), 3.12 (t, J=6.9 Hz, 2H), 3.18-3.38 (m, 2H),
5.38 (s, 2H), 6.82 (s, 1H), 6.94 (d, J=8.3 Hz, 1H), 7.03 (s, 1H),
7.15 (d, J=7.3 Hz, 1H), 7.23 (s, 1H), 7.27-7.46 (m, 8H), 7.56 (d,
J=8.3 Hz, 2H).
Example 64
(E)-2-[6-(2-Chlorophenyl)-4-methyl-2-propylbenzimidazol-1-yl]methyl-5-(1H--
tetrazol-5-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 64)
[0281] [step 1] Using 2-chlorophenylboronic acid (94 mg, 0.60 mmol)
instead of phenylboronic acid, and in the same manner as in Example
47, step 2,
(E)-{2-[6-(2-chlorophenyl)-4-methyl-2-propylbenzimidazol-1-yl]met-
hyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(68 mg, 64%) was obtained.
[0282] ESI-MS m/z: 528 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.95 (t, J=7.3 Hz, 3H), 1.69-1.83 (m, 2H), 2.55 (s, 3H),
2.82 (t, J=7.3 Hz, 2H), 3.01 (s, 4H), 5.46 (s, 2H), 6.12 (s, 1H),
6.90 (d, J=8.1 Hz, 1H), 7.02 (d, J=6.6 Hz, 2H), 7.26-7.41 (m, 9H),
7.48-7.52 (m, 1H).
[step 2] Using
(E)-{2-[6-(2-chlorophenyl)-4-methyl-2-propylbenzimidazol-1-yl]methyl-10,1-
1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (60 mg,
0.11 mmol) obtained in step 1 and in the same manner as in Example
4, the title compound (compound 64) (40 mg, 63%) was obtained.
[0283] ESI-MS m/z: 571 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.99 (t, J=7.3 Hz, 3H), 1.72-1.88 (m, 2H), 2.71 (s, 3H),
2.70-2.93 (br, 2H), 2.85 (t, J=7.3 Hz, 2H), 3.12-3.35 (br, 2H),
5.30 (s, 2H), 6.80 (s, 1H), 6.97 (d, J=8.1 Hz, 1H), 7.03 (s, 1H),
7.10 (s, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.20-7.43 (m, 9H).
Example 65
(E)-2-[6-(3-Chlorophenyl)-4-methyl-2-propylbenzimidazol-1-yl]methyl-5-(1H--
tetrazol-5-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 65)
[0284] [step 1] Using 3-chlorophenylboronic acid (94 mg, 0.60
mmol,) instead of phenylboronic acid, and in the same manner as in
Example 47, step 2,
(E)-{2-[6-(3-chlorophenyl)-4-methyl-2-propylbenzimidazol-1-yl]met-
hyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(47 mg, 45%) was obtained.
[0285] ESI-MS m/z: 528 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.94 (t, J=7.5 Hz, 3H), 1.67-1.82 (m, 2H), 2.58 (s, 3H),
2.78 (t, J=7.5 Hz, 2H), 2.96-3.09 (m, 4H), 5.54 (s, 2H), 6.12 (s,
1H), 6.82 (d, J=8.1 Hz, 1H), 7.02 (s, 1H), 7.23-7.48 (m, 8H),
7.59-7.65 (m, 2H), 7.68-7.72 (m, 1H).
[step 2] Using
(E)-{2-[6-(3-chlorophenyl)-4-methyl-2-propylbenzimidazol-1-yl]methyl-10,1-
1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (30 mg,
0.05 mmol) obtained in step 1 and in the same manner as in Example
4, the title compound (compound 65) (3.5 mg, 12%) was obtained.
[0286] ESI-MS m/z: 571 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.99 (t, J=7.3 Hz, 3H), 1.71-1.88 (m, 2H), 2.71 (s, 3H),
2.76-3.08 (br, 2H), 2.88 (t, J=7.3 Hz, 2H), 3.16-3.38 (br, 2H),
5.28 (s, 2H), 6.70 (s, 1H), 6.91 (d, J=8.1 Hz, 1H), 7.02 (s, 1H),
7.05 (s, 1H), 7.19 (d, J=7.7 Hz, 1H), 7.20-7.47 (m, 9H).
Example 66
(E)-2-[6-(4-Chlorophenyl)-4-methyl-2-propylbenzimidazol-1-yl]methyl-5-(1H--
tetrazol-5-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 66)
[0287] [step 1] Using 4-chlorophenylboronic acid (94 mg, 0.60 mmol)
instead of phenylboronic acid, and in the same manner as in Example
47, step 2,
(E)-{2-[6-(4-chlorophenyl)-4-methyl-2-propylbenzimidazol-1-yl]met-
hyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(55 mg, 52%) was obtained.
[0288] ESI-MS m/z: 528 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (t, J=7.6 Hz, 3H),
1.74-1.89 (m, 2H), 2.73 (s, 3H), 2.82 (t, J=7.6 Hz, 2H), 3.06 (s,
4H), 5.32 (s, 2H), 5.66 (s, 1H), 6.82 (s, 1H), 6.85 (d, J=8.4 Hz,
1H), 7.08 (s, 1H), 7.18-7.37 (m, 7H), 7.44 (t, J=8.1 Hz, 3H).
[step 2] Using
(E)-{2-[6-(4-chlorophenyl)-4-methyl-2-propylbenzimidazol-1-yl]methyl-10,1-
1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (40 mg,
0.08 mmol) obtained in step 1 and in the same manner as in Example
4, the title compound (compound 66) (21 mg, 47%) was obtained.
[0289] ESI-MS m/z: 571 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.00 (t, J=7.3 Hz, 3H), 1.73-1.89 (m, 2H), 2.71 (s, 3H),
2.74-3.01 (br, 2H), 2.84 (t, J=7.3 Hz, 2H), 3.16-3.40 (br, 2H),
5.33 (s, 2H), 6.76 (s, 1H), 6.94 (d, J=8.1 Hz, 1H), 7.05 (s, 1H),
7.11 (s, 1H), 7.17 (d, J=7.7 Hz, 1H), 7.27-7.50 (m, 9H).
Example 67
(E)-2-[4-Methyl-2-propyl-6-(2-thienyl)benzimidazol-1-yl]methyl-5-(1H-tetra-
zol-5-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 67)
[0290] [step 1]
(E)-[2-{6-Bromo-4-methyl-2-propylbenzimidazol-1-yl}methyl-10,11-dihydro-5-
H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (120 mg, 0.24
mmol) obtained in Example 47, step 1,2-thienyltetrabutyltin (268
mg, 0.72 mmol) and tetrakis(triphenylphosphine)palladium (92 mg,
0.08 mmol) were dissolved in toluene (2 mL), and the mixture was
stirred at 100.degree. C. for 2.5 hr. Water was added to the
mixture, and the mixture was extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/ethyl
acetate=7/3 to 7/7) to give
(E)-{2-[4-methyl-2-propyl-6-(2-thienyl)benzimidazol-1-yl]methyl-10,11-dih-
ydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (60 mg,
52%).
[0291] ESI-MS m/z: 500 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.00 (t, J=7.4 Hz, 3H), 1.72-1.89 (m, 2H), 2.70 (s, 3H),
2.81 (t, J=7.4 Hz, 2H), 3.06 (s, 4H), 5.30 (s, 2H), 5.67 (s, 1H),
6.82 (s, 1H), 6.87 (d, J=8.2 Hz, 1H), 7.03 (t, J=4.3 Hz, 1H),
7.12-7.24 (m, 3H), 7.27-7.48 (m, 5H), 7.59-7.68 (m, 1H).
[step 2] Using
(E)-{2-[4-methyl-2-propyl-6-(2-thienyl)benzimidazol-1-yl]methyl-10,11-dih-
ydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (60 mg, 0.06
mmol) obtained in step 1 and in the same manner as in Example 4,
the title compound (compound 67) (10 mg, 32%) was obtained.
[0292] ESI-MS m/z: 543 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.94 (t, J=7.3 Hz, 3H), 1.67-1.83 (m, 2H), 2.55 (s, 3H),
2.73-3.51 (br, 4H), 2.79 (t, J=7.6 Hz, 2H), 5.49 (s, 2H), 6.79 (s,
1H), 6.87 (t, J=6.4 Hz, 2H), 6.98-7.10 (m, 3H), 7.17-7.28 (m, 3H),
7.39-7.44 (m, 3H), 7.53 (s, 1H).
Example 68
(E)-2-[6-(2-Furanyl)-4-methyl-2-propylbenzimidazol-1-yl]methyl-5-(1H-tetra-
zol-5-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 68)
[0293] [step 1] Using 6-(2-furanyl)-4-methyl-2-propylbenzimidazole
(60 mg, 0.25 mmol) obtained in Reference Example A2 and in the same
manner as in Example 47, step 1,
(E)-{2-[6-(2-furanyl)-4-methyl-2-propylbenzimidazol-1-yl]methyl-10,11-dih-
ydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (10 mg, 30%)
was obtained.
[0294] ESI-MS m/z: 484 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.00 (t, J=7.3 Hz, 3H), 1.72-1.89 (m, 2H), 2.70 (s, 3H),
2.80 (t, J=7.3 Hz, 2H), 3.06 (s, 4H), 5.31 (s, 2H), 5.67 (s, 1H),
6.42-6.46 (m, 1H), 6.57 (d, J=3.3 Hz, 1H), 6.80 (s, 1H), 6.86 (d,
J=7.9 Hz, 1H), 7.16-7.24 (m, 2H), 7.27-7.35 (m, 3H), 7.36-7.48 (m,
3H).
[step 2] Using
(E)-{2-[6-(2-furanyl)-4-methyl-2-propylbenzimidazol-1-yl]methyl-10,11-dih-
ydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (30 mg, 0.06
mmol) obtained in step 1 and in the same manner as in Example 4,
the title compound (compound 68) (10 mg, 30%) was obtained.
[0295] ESI-MS m/z: 527 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.98 (t, J=7.3 Hz, 3H), 1.71-1.86 (m, 2H), 2.65 (s, 3H),
2.71-2.97 (m, 2H), 2.80 (t, J=7.3 Hz, 2H), 3.10-3.43 (m, 2H), 5.32
(s, 2H), 6.42-6.46 (m, 1H), 6.57 (d, J=2.9 Hz, 1H), 6.73 (s, 1H),
6.94 (d, J=8.1 Hz, 1H), 7.03 (s, 1H), 7.16 (d, J=7.3 Hz, 1H),
7.30-7.43 (m, 7H).
Example 69
(E)-2-[4-Methyl-6-(1,3-oxazol-2-yl)-2-propylbenzimidazol-1-yl]methyl-5-(1H-
-tetrazol-5-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 69)
[0296] [step 1] Using 2-ethyl-6-(oxazol-2-yl)-4-methylbenzimidazole
(207 mg, 0.85 mmol) obtained in Reference Example A3 and in the
same manner as in Example 47, step 1,
(E)-{2-[4-methyl-6-(oxazol-2-yl)-2-propylbenzimidazol-1-yl]methyl-10,11-d-
ihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (285 mg,
69%) was obtained.
[0297] ESI-MS m/z: 485 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.94 (t, J=7.4 Hz, 3H), 1.72-1.83 (m, 2H), 2.59 (s, 3H),
2.82 (t, J=7.4 Hz, 2H), 3.02 (s, 4H), 5.55 (s, 2H), 6.13 (s, 1H),
6.81 (d, J=7.6 Hz, 1H), 6.99 (s, 1H), 7.25-7.39 (m, 6H), 7.65 (s,
1H), 7.81 (s, 1H), 8.13 (s, 1H).
[step 2] Using
(E)-{2-[4-methyl-6-(oxazol-2-yl)-2-propylbenzimidazol-1-yl]methyl-10,11-d-
ihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (100 mg,
0.21 mmol) obtained in step 1 and in the same manner as in Example
4, the title compound (compound 69) (48 mg, 43%) was obtained.
[0298] ESI-MS m/z: 528 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.94 (t, J=7.4 Hz, 3H), 1.72-1.83 (m, 2H), 2.59 (s, 3H),
2.82 (t, J=7.4 Hz, 2H), 3.02 (s, 4H), 5.55 (s, 2H), 6.13 (s, 1H),
6.81 (d, J=7.6 Hz, 1H), 6.99 (s, 1H), 7.25-7.39 (m, 6H), 7.65 (s,
1H), 7.81 (s, 1H), 8.13 (s, 1H).
Example 70
(E)-2-[4-Methyl-6-(1,3,4-oxadiazol-2-yl)-2-propylbenzimidazol-1-yl]methyl--
5-(1H-tetrazol-5-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 70)
[0299] [step 1]
(E)-[2-(6-Carboxy-4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-
-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (274 mg, 0.59
mmol) obtained in Reference Example B8 was dissolved in
dichloromethane (1 mL), N,N'-carbonyldiimidazole (CDI) (107 mg,
0.66 mmol) was added, and the mixture was stirred at room
temperature for 20 min. To this mixture was added hydrazine
monohydrate (89 mg, 1.77 mmol), and the mixture was stirred at room
temperature for 3 hr. The mixture was concentrated under reduced
pressure, water (20 mL) was added, and the precipitate was
collected by filtration to give
(E)-{2-[4-methyl-6-(hydrazinocarbonyl)-2-propylbenzimidazol-1-yl]methyl-1-
0,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (246
mg, 88%).
[0300] ESI-MS m/z: 476 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.01 (t, J=7.3 Hz, 3H), 1.75-1.90 (m, 2H), 2.71 (s, 3H),
2.83 (t, J=7.3 Hz, 2H), 3.06 (s, 4H), 5.33 (s, 2H), 5.66 (s, 1H),
6.75-6.87 (m, 2H), 7.19-7.44 (m, 6H), 7.65 (s, 1H), 8.50-8.73 (m,
1H).
[step 2]
(E)-{2-[4-Methyl-6-(hydrazinocarbonyl)-2-propylbenzimidazol-1-yl-
]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(40 mg, 0.08 mmol) obtained in step 1 was suspended in acetic acid
(3 mL), triethyl orthoformate (3 ml) was added, and the mixture was
stirred at 50.degree. C. for 6 hr. Water (10 mL) was added to the
mixture, and the mixture was neutralized to pH 9 with 30% aqueous
ammonia solution, and extracted twice with chloroform. The organic
layer was washed with brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography
(chloroform:methanol=9:1) to give
(E)-{2-[4-methyl-6-(1,3,4-oxadiazol-2-yl)-2-propylbenzimidazol-1-yl]methy-
l-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(24 mg, 58%).
[0301] ESI-MS m/z: 486 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.02 (t, J=7.3 Hz, 3H), 1.76-1.90 (m, 2H), 2.71 (s, 3H),
2.86 (t, J=7.3 Hz, 2H), 3.08 (s, 4H), 5.43 (s, 2H), 5.76 (s, 1H),
6.86 (d, J=6.2 Hz, 2H), 7.24-7.41 (m, 5H), 7.76 (s, 2H), 8.72 (s,
1H).
[step 3] Using
(E)-{2-[4-methyl-6-(1,3,4-oxadiazol-2-yl)-2-propylbenzimidazol-1-yl]methy-
l-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(65 mg, 0.13 mmol) obtained in step 2 and in the same manner as in
Example 4, the title compound (compound 70) (4.4 mg, 6.4%) was
obtained.
[0302] ESI-MS m/z: 529 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.96 (t, J=7.4 Hz, 3H), 1.68-1.86 (m, 2H), 2.64 (s, 3H),
2.76-3.42 (br, 4H), 2.96 (t, J=7.4 Hz, 2H), 5.68 (s, 2H), 6.80 (s,
1H), 6.87 (d, J=7.5 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 7.00-7.06 (m,
2H), 7.15-7.28 (m, 2H), 7.42 (d, J=8.1 Hz, 1H), 7.80 (s, 1H), 8.05
(s, 1H), 9.30 (s, 1H).
Example 71
(E)-2-[4-Methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-2-propylbenzimidazol-1-y-
l]methyl-5-(1H-tetrazol-5-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloh-
eptene (Compound 71)
[0303] [step 1] Using
(E)-{2-[4-methyl-6-(hydrazinocarbonyl)-2-propylbenzimidazol-1-yl]methyl-1-
0,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (150
mg, 0.32 mmol) obtained in Example 70, step 1, and triethyl
orthoacetate (10.5 mL) instead of triethyl orthoformate, and in the
same manner as in Example 70, step 2,
(E)-{2-[4-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-2-propylbenzimidazol-1-
-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(100 mg, 62%) was obtained.
[0304] ESI-MS m/z: 500 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.02 (t, J=7.4 Hz, 3H), 1.74-1.92 (m, 2H), 2.58 (s, 3H),
2.73 (s, 3H), 2.83 (t, J=7.8 Hz, 2H), 3.06 (s, 4H), 5.35 (s, 2H),
5.67 (s, 1H), 6.78 (s, 1H), 6.83 (d, J=7.9 Hz, 1H), 7.18-7.37 (m,
4H), 7.43 (d, J=7.9 Hz, 1H), 7.72 (s, 2H).
[step 2] Using
(E)-{2-[4-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-2-propylbenzimidazol-1-
-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(50 mg, 0.10 mmol) obtained in step 1 and in the same manner as in
Example 5, the title compound (compound 71) (43 mg, 79%) was
obtained.
[0305] ESI-MS m/z: 543 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.03 (t, J=7.2 Hz, 3H), 1.76-1.94 (m, 2H), 2.62 (s, 3H),
2.76 (s, 3H), 2.77-3.04 (br, 2H), 3.15-3.44 (br, 2H), 3.19 (t,
J=7.2 Hz, 2H), 5.49 (s, 2H), 6.81 (s, 1H), 6.96 (d, J=7.9 Hz, 1H),
7.02 (s, 1H), 7.12 (d, J=7.6 Hz, 1H), 7.20-7.25 (m, 1H), 7.33-7.43
(m, 2H), 7.48 (d, J=7.9 Hz, 1H), 7.91 (d, J=4.3 Hz, 2H).
Example 72
(E)-{2-[4-Methyl-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-propylbenzim-
idazol-1-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acet-
onitrile (Compound 72)
[0306]
(E)-{2-[4-Methyl-6-(hydrazylcarbonyl)-2-propylbenzimidazol-1-yl]met-
hyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(150 mg, 0.32 mmol) obtained in Example 70, step 1 was dissolved in
methylene chloride (2 mL), N,N'-carbonyldiimidazole (68 mg, 0.42
mmol) was added, and the mixture was stirred at room temperature
for 4 hr. Acetic acid (2 mL) was added to the mixture, and the
mixture was stirred at 60.degree. C. for 6 hr. The mixture was
concentrated under reduced pressure, and the residue was purified
by reversed-phase liquid chromatography (water/acetonitrile=7/3 to
1/9) to give the title compound (compound 72) (12 mg, 12%).
[0307] ESI-MS m/z: 502 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.04 (t, J=7.4 Hz, 3H), 1.80-1.96 (m, 2H), 2.53 (s, 3H),
3.04-3.22 (m, 6H), 5.43 (s, 2H), 5.69 (s, 1H), 6.95-7.02 (m, 2H),
7.18-7.23 (m, 2H), 7.29-7.35 (m, 4H), 7.44 (d, J=7.2 Hz, 1H), 11.04
(br s, 1H).
Example 73
(Z)-3-(2,5,7-Trimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-11-[1-(1H-tetr-
azol-5-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine (Compound
73)
[0308] [step 1]
(Z)-2-(3-Hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propiono-
nitrile (400 mg, 1.44 mmol) obtained in Reference Example B6 and
2,5,7-trimethyl-3H-imidazo[4,5-b]pyridine (U.S. Pat. No. 5,332,744;
349 mg, 2.16 mmol) were dissolved in THF (14 mL), polymer-supported
triphenylphosphine (962 mg, 2.88 mmol) and di-tert-butyl
azodicarboxylate (664 mg, 2.88 mmol) were added at 0.degree. C.,
and the mixture was stirred at room temperature for 2 hr. The
mixture was filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=4/6) to give
(Z)-2-[3-(2,5,7-trimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,-
11-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (310 mg,
51%).
[0309] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.94 (s, 3H), 2.42 (s,
3H), 2.47 (s, 3H), 2.48 (s, 3H), 4.91 (d, J=12.6 Hz, 1H), 5.37 (2H,
s), 5.42 (d, J=12.6 Hz, 1H), 6.47 (d, J=1.6 Hz, 1H), 6.72 (dd,
J=8.1, 1.8 Hz, 1H), 6.93 (s, 1H), 7.26-7.54 (m, 5H).
[step 2] Using
(Z)-2-[3-(2,5,7-trimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dihyd-
rodibenzo[b,e]oxepin-11-ylidene]propiononitrile (153 mg, 0.364
mmol) obtained in step 1 and in the same manner as in Example 4,
the title compound (compound 73) (106 mg, 63%) was obtained.
[0310] ESI-MS m/z: 464 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 2.06 (s, 3H), 2.35 (s, 3H), 2.46 (s, 6H), 4.91 (d, J=12.3
Hz, 1H), 5.26 (s, 2H), 5.71 (d, J=12.3 Hz, 1H), 6.34-6.41 (m, 3H),
6.91 (s, 1H), 7.38-7.53 (m, 4H).
Example 74
(Z)-3-(2,5,7-Trimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-11-[1-(5-oxo-4-
,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepin-
e (Compound 74)
[0311] Using
(Z)-2-[3-(2,5,7-trimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dihyd-
rodibenzo[b,e]oxepin-11-ylidene]propiononitrile (153 mg, 0.364
mmol) obtained in Example 73, step 1 and in the same manner as in
Example 5, the title compound (compound 74) (36 mg, 21%) was
obtained.
[0312] ESI-MS m/z: 480 (M+H).sup.+, .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 1.98 (s, 3H), 2.38 (s, 3H), 2.47 (s, 6H), 4.86 (d, J=12.3
Hz, 1H), 5.32 (s, 2H), 5.59 (d, J=12.3 Hz, 1H), 6.38 (d, J=1.6 Hz,
1H), 6.61 (dd, J=8.1, 1.8 Hz, 1H), 6.91-6.92 (m, 2H), 7.30-7.51 (m,
4H).
Example 75
(Z)-3-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-11-[1-(1H-
-tetrazol-5-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine
(Compound 75)
[0313] [step 1] Using
2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (U.S. Pat. No.
5,332,744; 284 mg, 1.62 mmol) instead of
2,5,7-trimethyl-3H-imidazo[4,5-b]pyridine, and in the same manner
as in Example 73, step 1,
(Z)-2-[3-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11--
dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (271 mg, 38%)
was obtained.
[0314] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.31 (t, J=7.6 Hz, 3H),
2.01 (s, 3H), 2.55 (s, 3H), 2.61 (d, J=0.5 Hz, 3H), 2.75 (q, J=7.6
Hz, 2H), 4.77 (d, J=12.6 Hz, 1H), 5.33-5.39 (m, 2H), 5.43 (d,
J=12.6 Hz, 1H), 6.47 (d, J=1.7 Hz, 1H), 6.73 (dd, J=8.1, 1.8 Hz,
1H), 6.86 (s, 1H), 7.12-7.16 (m, 1H), 7.36-7.37 (m, 3H), 7.44 (d,
J=7.9 Hz, 1H).
[step 2] Using
(Z)-2-[3-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11--
dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (270 mg, 0.621
mmol) obtained in step 1 and in the same manner as in Example 4,
the title compound (compound 75) (159 mg, 54%) was obtained.
[0315] ESI-MS m/z: 478 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 1.18 (t, J=7.5 Hz, 3H), 2.06 (s, 3H), 2.46 (s, 3H), 2.49
(s, 3H), 2.66 (q, J=7.5 Hz, 2H), 4.91 (d, J=12.3 Hz, 1H), 5.27 (s,
2H), 5.71 (d, J=12.3 Hz, 1H), 6.33-6.38 (m, 3H), 6.92 (s, 1H),
7.38-7.53 (m, 4H).
Example 76
(Z)-3-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-11-[1-(5--
oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]o-
xepine (Compound 76)
[0316] Using
(Z)-2-[3-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11--
dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (150 mg, 0.345
mmol) obtained in Example 75, step 1 and in the same manner as in
Example 5, the title compound (compound 76) (107 mg, 63%) was
obtained.
[0317] ESI-MS m/z: 494 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 1.19 (t, J=7.5 Hz, 3H), 1.98 (s, 3H), 2.47 (s, 3H), 2.49
(s, 3H), 2.69 (q, J=7.5 Hz, 2H), 4.86 (d, J=12.5 Hz, 1H), 5.33 (s,
2H), 5.59 (d, J=12.5 Hz, 1H), 6.39 (d, J=1.6 Hz, 1H), 6.58 (dd,
J=8.1, 1.8 Hz, 1H), 6.89-6.92 (m, 2H), 7.30-7.51 (m, 4H).
Example 77
(Z)-3-(2-Cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-11-[1-(-
1H-tetrazol-5-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine
(Compound 77)
[0318] [step 1] Using
2-cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridine (U.S. Pat. No.
5,332,744; 656 mg, 3.79 mmol) instead of
2,5,7-trimethyl-3H-imidazo[4,5-b]pyridine, and in the same manner
as in Example 73, step 1,
(Z)-2-[3-(2-cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,1-
1-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (274 mg,
17%) was obtained.
[0319] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.01-1.08 (m, 4H), 1.93
(s, 3H), 2.19-2.22 (m, 1H), 2.49 (s, 3H), 4.92 (d, J=12.7 Hz, 1H),
5.42 (d, J=12.7 Hz, 1H), 5.53 (s, 2H), 6.60 (d, J=1.5 Hz, 1H), 6.81
(dd, J=8.1, 1.8 Hz, 1H), 7.03 (dd, J=4.9, 0.8 Hz, 1H), 7.26-7.29
(m, 1H), 7.41-7.54 (m, 4H), 8.08 (d, J=4.9 Hz, 1H).
[step 2] Using
(Z)-2-[3-(2-cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,1-
1-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (135 mg,
0.312 mmol) obtained in step 1 and in the same manner as in Example
4, the title compound (compound 77) (71 mg, 48%) was obtained.
[0320] ESI-MS m/z: 476 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.96-1.00 (m, 4H), 2.06 (s, 3H), 2.08-2.15 (m, 1H), 2.47
(s, 3H), 4.92 (d, J=12.3 Hz, 1H), 5.41 (s, 2H), 5.71 (d, J=12.3 Hz,
1H), 6.37-6.49 (m, 3H), 7.01 (d, J=4.9 Hz, 1H), 7.38-7.53 (m, 4H),
8.06 (d, J=304.9 Hz, 1H).
Example 78
(Z)-3-(2-Cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-11-[1-(-
5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e-
]oxepine (Compound 78)
[0321] Using
(Z)-2-[3-(2-cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,1-
1-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (135 mg,
0.312 mmol) obtained in Example 77, step 1 and in the same manner
as in Example 5, the title compound (compound 78) (83 mg, 54%) was
obtained.
[0322] ESI-MS m/z: 492 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.99-1.00 (m, 4H), 1.98 (s, 3H), 2.14-2.16 (m, 1H), 2.48
(s, 3H), 4.86 (d, J=12.3 Hz, 1H), 5.47 (s, 2H), 5.59 (d, J=12.3 Hz,
1H), 6.52 (d, J=1.6 Hz, 1H), 6.69 (dd, J=8.1, 1.6 Hz, 1H), 6.92 (d,
J=8.1 Hz, 1H), 7.02 (d, J=5.4 Hz, 1H), 7.30-7.51 (m, 4H), 8.07 (d,
J=4.9 Hz, 1H).
Example 79
(E)-2-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-4-(1H-tet-
razol-5-yl)methylene-4H-9,10-dihydrobenzo[4,5]cyclohepta[1,2-b]thiophene
(Compound 79)
[0323] [step 1] Using
(E)-(2-hydroxymethyl-4H-9,10-dihydrobenzo[4,5]cyclohepta[1,2-b]thiophen-4-
-ylidene)acetonitrile (200 mg, 0.748 mmol) obtained in Reference
Example B7 instead of
(Z)-2-(3-hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propiono-
nitrile, and in the same manner as in Example 73, step 1,
(E)-[2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-4H-9,10-
-dihydrobenzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene]acetonitrile
(120 mg, 38%) was obtained.
[0324] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.41 (t, J=7.5 Hz, 3H),
2.61 (s, 6H), 2.90 (q, J=7.5 Hz, 2H), 3.02 (s, 4H), 5.46 (s, 2H),
5.65 (s, 1H), 6.81 (s, 1H), 6.89 (s,) 1H, 7.21-7.37 (m, 3H),
7.46-7.49 (m, 1H).
[step 2] Using
(E)-[2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-4H-9,10-
-dihydrobenzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene]acetonitrile
(65 mg, 0.153 mmol) obtained in step 1 and in the same manner as in
Example 4, the title compound (compound 79) (42 mg, 59%) was
obtained.
[0325] ESI-MS m/z: 468 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.39 (t, J=7.6 Hz, 3H), 2.57 (s, 3H), 2.61 (s, 3H),
2.84-2.95 (m, 4H), 3.12-3.23 (m, 2H), 5.49 (d, J=3.3 Hz, 2H), 6.90
(s, 1H), 6.98 (d, J=7.4 Hz, 2H), 7.14 (d, J=7.4 Hz, 1H), 7.24-7.43
(m, 3H).
Example 80
(E)-2-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-4-(5-oxo--
4,5-dihydro-1,2,4-oxadiazol-3-yl)methylene-4H-9,10-dihydrobenzo[4,5]cycloh-
epta[1,2-b]thiophene (Compound 80)
[0326] Using
(E)-[2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-4H-9,10-
-dihydrobenzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene]acetonitrile
(62 mg, 0.147 mmol) obtained in Example 79, step 1 and in the same
manner as in Example 5, the title compound (compound 80) (61 mg,
85%) was obtained.
[0327] ESI-MS m/z: 484 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.41 (t, J=7.6 Hz, 3H), 2.61 (s, 6H), 2.84-2.95 (m, 4H),
3.16-3.30 (m, 2H), 5.48 (s, 2H), 6.45 (s, 1H), 6.87-6.89 (m, 2H),
7.17 (dd, J=7.4, 1.0 Hz, 1H), 7.26-7.44 (m, 3H).
Example 81
(Z)-2-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-4-(1H-tet-
razol-5-yl)methylene-4H-9,10-dihydrobenzo[4,5]cyclohepta[1,2-b]thiophene
(Compound 81)
[0328] [step 1] Using
(Z)-(2-hydroxymethyl-4H-9,10-dihydrobenzo[4,5]cyclohepta[1,2-b]thiophen-4-
-ylidene)acetonitrile (200 mg, 0.748 mmol) obtained in Reference
Example B7 and in the same manner as in Example 79, step 1,
(Z)-[2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-4H-9,10-
-dihydrobenzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene]acetonitrile
(126 mg, 40%) was obtained.
[0329] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.41 (t, J=7.5 Hz, 3H),
2.60 (s, 6H), 2.95 (q, J=7.5 Hz, 2H), 3.01-3.08 (m, 4H), 5.43 (s,
1H), 5.52 (s, 2H), 6.87 (s, 1H), 7.16-7.33 (m, 4H), 7.45 (s,
1H).
[step 2] Using
(Z)-[2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-4H-9,10-
-dihydrobenzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene]acetonitrile
(65 mg, 0.153 mmol) obtained in step 1 and in the same manner as in
Example 4, the title compound (compound 81) (57 mg, 80%) was
obtained.
[0330] ESIMS m/z: 468 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.33 (t, J=7.6 Hz, 3H), 2.53 (s, 3H), 2.59 (s, 3H), 2.80
(q, J=7.6 Hz, 2H), 2.99 (s, 4H), 5.37 (s, 2H), 6.41 (s, 1H), 6.73
(s, 1H), 6.89 (s, 1H), 7.17-7.33 (m, 4H).
Example 82
(Z)-2-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-4-(5-oxo--
4,5-dihydro-1,2,4-oxadiazol-3-yl)methylene-4H-9,10-dihydrobenzo[4,5]cycloh-
epta[1,2-b]thiophene (Compound 82)
[0331] Using
(Z)-[2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-4H-9,10-
-dihydrobenzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene]acetonitrile
(63 mg, 0.148 mmol) obtained in Example 81, step 1 and in the same
manner as in Example 5, the title compound (compound 82) (54 mg,
75%) was obtained.
[0332] ESI-MS m/z: 484 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.39 (t, J=7.6 Hz, 3H), 2.57 (s, 3H), 2.59 (s, 3H), 2.86
(q, (7=7.6 Hz, 2H), 3.02-3.09 (m, 4H), 5.45 (s, 2H), 6.24 (s, 1H),
6.67 (s, 1H), 6.88 (s, 1H), 7.19-7.30 (m, 4H).
Example 83
(E)-2-[1-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ethyl]-5-(1H--
tetrazol-5-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 83)
[0333] [step 1]
(E)-(2-Hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)a-
cetonitrile (JP-B-2526005; 523 mg, 2.00 mmol) was dissolved in
dichloromethane (5 mL),
1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.10 g,
2.60 mmol) was added at 0.degree. C., and the mixture was stirred
at room temperature for 45 min. Isopropyl alcohol (0.5 mL) and
water were added to the mixture, and the mixture was extracted with
ethyl acetate. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=70/30 to 0/100) to give
(E)-(2-formyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonit-
rile (518 mg, 100%).
[0334] .sup.1H-NMR (CDCl.sub.3, .delta.): 3.16-3.24 (m, 4H), 5.76
(s, 1H), 7.23-7.39 (m, 3H), 7.45 (d, (7=8.1 Hz, 1H), 7.49 (dd,
J=7.3, 1.5 Hz, 1H), 7.68 (s, 1H), 7.73 (dd, J=7.7, 1.5 Hz, 1H),
9.99 (s, 1H).
[step 2]
(E)-(2-Formyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene-
)acetonitrile (218 mg, 0.84 mmol) obtained in step 1 was dissolved
in THF (4 mL), methylmagnesium chloride (3 mol/L THF solution; 0.42
mL, 1.26 mmol) was added at -78.degree. C., and the mixture was
warmed to -10.degree. C. over 40 min. Saturated aqueous ammonium
chloride solution was added to the mixture, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate=100/0 to 50/50) to give
(E)-[2-(1-hydroxyethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yliden-
e]acetonitrile (212 mg, 92%).
[0335] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.42 (d, J=6.3 Hz, 3H),
3.02-3.15 (m, 4H), 4.81 (q, J=6.3 Hz, 1H), 5.68 (s, 1H), 7.13-7.44
(m, 7H).
[step 3]
(E)-[2-(1-Hydroxyethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-
-5-ylidene]acetonitrile (100 mg, 0.36 mmol) obtained in step 2 and
2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (193 mg, 1.10 mmol)
were dissolved in THF (1.5 mL), polymer-supported
triphenylphosphine (734 mg, 15 mmol) and di-tert-butyl
azodicarboxylate (70 mg, 0.305 mmol) were added, and the mixture
was stirred at room temperature for 1 hr. The mixture was filtered,
and the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(hexane/ethyl acetate=40/60 to 30/70) to give
(E)-{2-[1-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ethyl]-10,1-
1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (71 mg,
45%).
[0336] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.27 (t, J=7.4 Hz,) 3H,
2.01 (d, J=7.2 Hz, 3H), 2.56 (s, 3H), 2.57-2.79 (m, 2H), 2.61 (s,
3H), 3.04-3.08 (m, 4H), 5.68 (s, 1H), 6.07 (q, J=7.2 Hz, 1H), 6.87
(s, 1H), 7.02 (s, 1H), 7.07-7.35 (m, 5H), 7.44 (dd, J=7.1, 1.5 Hz,
1H).
[step 4] Using
(E)-{2-[1-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ethyl]-10,1-
1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (25 mg,
0.081 mmol) obtained in step 3 and in the same manner as in Example
4, the title compound (compound 83) (20 mg, 52%) was obtained.
[0337] ESI-MS m/z: 476 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.24 (t, J=7.6 Hz, 3H), 2.02 (d, J=7.3 Hz, 3H), 2.56 (s,
3H), 2.57 (s, 3H), 2.58-3.00 (m, 4H), 3.23 (m, 2H), 6.09 (q, J=7.3
Hz, 1H), 6.87 (s, 1H), 6.91-7.50 (m, 8H).
Example 84
(E)-2-[1-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ethyl]-5-(5-o-
xo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d-
]cycloheptene (Compound 84)
[0338] Using
(E)-{2-[1-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ethyl]-10,1-
1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (30 mg,
0.083 mmol) obtained in Example 83, step 3 and in the same manner
as in Example 5, the title compound (compound 84) (23 mg, 57%) was
obtained.
[0339] ESI-MS m/z: 492 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.27 (t, J=7.6 Hz, 3H), 2.02 (d, J=7.6 Hz, 3H), 2.56 (s,
3H), 2.61 (s, 3H), 2.60-3.01 (m, 4H), 3.15-3.42 (m, 2H), 6.06 (q,
J=7.2 Hz, 1H), 6.50 (s, 1H), 6.87 (s, 1H), 7.00 (m, 1H), 7.07-7.46
(m, 6H).
Example 85
(E)-2-[1-(2-Propyl-4-methylbenzimidazol-1-yl)ethyl]-5-(5-oxo-4,5-dihydro-1-
,2,4-oxadiazol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 85)
[0340] [step 1]
(E)-[2-(1-Hydroxyethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yliden-
e]acetonitrile (67 mg, 0.24 mmol) obtained in Example 83, step 2
was dissolved in dichloromethane (1 mL), boron tribromide (1.0
mol/L dichloromethane solution; 0.73 mL, 0.73 mmol) was added at
0.degree. C., and the mixture was stirred for 20 min. Water was
added to the mixture, and the mixture was extracted with ethyl
acetate. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The obtained residue was dissolved in DMA (0.5 mL),
2-propyl-4-methylbenzimidazole (63 mg, 0.36 mmol) and potassium
carbonate (100 mg, 0.72 mmol) were added, and the mixture was
stirred at 70.degree. C. for 4 hr. Water was added to the mixture,
and the mixture was extracted with ethyl acetate. The organic layer
was washed with brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate=50/50) to
give
(E)-{2-[1-(2-propyl-4-methylbenzimidazol-1-yl)ethyl]-10,11-dihydro-5H-dib-
enzo[a,d]cyclohepten-5-ylidene}acetonitrile (46 mg, 45%).
[0341] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.03 (t, J=7.4 Hz, 3H),
1.77-1.86 (m, 2H), 1.94 (d, J=7.3 Hz, 3H), 2.66 (s, 3H), 2.91 (t,
J=8.0 Hz, 2H), 3.07 (br s, 4H), 5.68 (q, J=7.3 Hz, 1H), 5.69 (s,
1H), 6.75-6.76 (m, 1H), 6.89-7.02 (m, 4H), 7.24-7.31 (m, 4H),
7.42-7.45 (m, 1H).
[step 2] Using
(E)-{2-[1-(2-propyl-4-methylbenzimidazol-1-yl)ethyl]-10,11-dihydro-5H-dib-
enzo[a,d]cyclohepten-5-ylidene}acetonitrile (45 mg, 0.104 mmol)
obtained in step 1 and in the same manner as in Example 5, the
title compound (compound 85) (23 mg, 45%) was obtained.
[0342] ESI-MS m/z: 491 (M+H).sup.+; .sup.1H-NMR(CDCl.sub.3,
.delta.): 1.02 (t, J=7.3 Hz, 3H), 1.75-1.86 (m, 2H), 1.94 (d, J=7.0
Hz, 3H), 2.65 (s, 3H), 2.80-2.97 (m, 4H), 3.16-3.38 (m, 2H), 5.67
(q, J=7.0 Hz, 1H), 6.50 (d, J=4.8 Hz, 1H), 6.77 (d, J=7.3 Hz, 1H),
6.88-6.99 (m, 3H), 7.04 (d, J=8.1 Hz, 1H), 7.17 (d, J=6.6 Hz, 1H),
7.30-7.42 (m, 4H).
Example 86
(E)-2-[1-(2-Propyl-4-methylbenzimidazol-1-yl)butyl]-5-(5-oxo-4,5-dihydro-1-
,2,4-oxadiazol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 86)
[0343] [step 1] Using
(E)-(2-formyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonit-
rile (245 mg, 0.95 mmol) obtained in Example 83, step 1, and
propylmagnesium bromide (2.0 mol/L THF solution; 0.71 mL, 1.42
mmol) instead of methylmagnesium chloride, and in the same manner
as in Example 83, step 2,
(E)-[2-(1-hydroxybutyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yliden-
e]acetonitrile (184 mg, 64%) was obtained.
[0344] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.92 (t, J=7.3 Hz, 3H),
1.28-1.48 (m, 2H), 1.58-1.77 (m, 2H), 3.06-3.18 (m, 4H), 4.62-4.68
(m, 1H), 5.71 (s, 1H), 7.13-7.36 (m, 6H), 7.45 (dd, J=7.5, 1.6 Hz,
1H).
[step 2] Using
(E)-[2-(1-hydroxybutyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yliden-
e]acetonitrile (184 mg, 0.61 mmol) obtained in step 1 and in the
same manner as in Example 85, step 1,
(E)-{2-[1-(2-propyl-4-methylbenzimidazol-1-yl)butyl]-10,11-dihydro-5H-dib-
enzo[a,d]cyclohepten-5-ylidene}acetonitrile (56 mg, 20%) was
obtained.
[0345] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.91 (t, J=7.1 Hz, 3H),
1.01 (t, J=7.3 Hz, 3H), 1.28-1.34 (m, 1H), 1.74-1.89 (m, 3H),
2.29-2.50 (m, 2H), 2.67 (s, 3H), 2.85-2.91 (m, 2H), 3.07 (br s,
4H), 5.48 (dd, J=10.3, 5.1 Hz, 1H), 5.68 (s, 1H), 6.89-7.02 (m,
5H), 7.18-7.35 (m, 4H), 7.44 (dd, J=7.1, 1.6 Hz, 1H).
[step 3] Using
(E)-{2-[1-(2-propyl-4-methylbenzimidazol-1-yl)butyl]-10,11-dihydro-5H-dib-
enzo[a,d]cyclohepten-5-ylidene}acetonitrile (56 mg, 0.122 mmol)
obtained in step 2 and in the same manner as in Example 5, the
title compound (compound 86) (30 mg, 47%) was obtained.
[0346] ESI-MS m/z: 519 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.93 (t, J=7.2 Hz, 3H), 1.00 (t, J=7.2 Hz, 3H), 1.20-1.73
(m, 2H), 1.80 (m, 2H), 2.39 (m, 2H), 2.66 (s, 3H), 2.72-3.00 (m,
4H), 3.28 (m, 2H), 5.47 (dd, J=5.3, 9.9 Hz, 1H), 6.49 (m, 1H),
6.80-7.54 (m, 10H).
Example 87
(E)-2-[1-(4-Chloro-2-ethylbenzimidazol-1-yl)ethyl]-5-(5-oxo-4,5-dihydro-1,-
2,4-oxadiazol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 87)
[0347] [step 1]
(E)-[2-(1-Hydroxyethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yliden-
e]acetonitrile (0.228 g, 0.829 mmol) obtained in Example 83, step 2
was dissolved in dichloromethane (4 mL), boron tribromide (1 mol/L
dichloromethane solution, 2.5 mL, 2.48 mmol) was added, and the
mixture was stirred at room temperature for 1 hr. Water was added
to the reaction mixture, and the mixture was extracted three times
with ethyl acetate. The combined organic layers were dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure to give a residue.
[0348] 4-Chloro-2-ethylbenzimidazole (0.164 g, 0.912 mmol) was
dissolved in DMA (3 mL), potassium carbonate (0.340 g, 2.49 mmol)
was added, and the mixture was stirred for 15 min. To this mixture
was added the residue obtained above, and the mixture was stirred
at 60.degree. C. for 2 hr. Water was added to the mixture, and the
mixture was extracted three times with ethyl acetate. The combined
organic layers were dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane/ethyl
acetate=1/2) to give
(E)-{2-[1-(4-chloro-2-ethylbenzimidazol-1-yl)ethyl]-10,11-dihydro-5H-dibe-
nzo[a,d]cyclohepten-5-ylidene}acetonitrile (0.118 g, 32%).
[step 2] Using
(E)-{2-[1-(4-chloro-2-ethylbenzimidazol-1-yl)ethyl]-10,11-dihydro-5H-dibe-
nzo[a,d]cyclohepten-5-ylidene}acetonitrile (0.118 g, 0.269 mmol)
obtained in step 1 and in the same manner as in Example 5, the
title compound (compound 87) (0.035 g, 28%) was obtained.
[0349] ESI-MS m/z: 497 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.43 (t, J=7.6 Hz, 3H), 1.96 (d, J=7.0 Hz, 3H), 2.75-3.07
(m, 4H), 3.10-3.49 (m, 2H), 5.70 (q, J=7.0 Hz, 1H), 6.48-6.58 (m,
1H), 6.67-6.79 (m, 1H), 6.79-6.90 (m, 2H), 6.90-7.02 (m, 1H),
7.02-7.11 (m, 1H), 7.14-7.25 (m, 2H), 7.24-7.50 (m, 3H).
Example 88
(E)-2-[1-(4-Chloro-2-cyclopropylbenzimidazol-1-yl)ethyl]-5-(5-oxo-4,5-dihy-
dro-1,2,4-oxadiazol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cyclohepte-
ne (Compound 88)
[0350] [step 1] Using 4-chloro-2-cyclopropylbenzimidazole (0.164 g,
0.912 mmol) instead of 4-chloro-2-ethylbenzimidazole, and in the
same manner as in Example 87, step 1,
(E)-{2-[1-(4-chloro-2-cyclopropylbenzimidazol-1-yl)ethyl]-10,11-dihydro-5-
H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (0.270 g, 72%) was
obtained. [step 2] Using
(E)-{2-[1-(4-chloro-2-cyclopropylbenzimidazol-1-yl)ethyl]-10,11-dihydro-5-
H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (0.270 g, 0.600
mmol) obtained in step 1 and in the same manner as in Example 5,
the title compound (compound 88) (0.004 g, 1.3%) was obtained.
[0351] ESI-MS m/z: 509 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.84-1.04 (m, 2H), 1.09-1.26 (m, 2H), 1.71-1.91 (m, 4H),
2.62-2.95 (m, 2H), 3.01-3.32 (m, 2H), 5.86 (q, J=7.0 Hz, 1H),
6.33-6.45 (m, 1H), 6.57-6.68 (m, 1H), 6.70-6.91 (m, 2H), 6.93-7.37
(m, 7H).
Example 89
(E)-2-[1-(4-Chloro-2-propylbenzimidazol-1-yl)ethyl]-5-(5-oxo-4,5-dihydro-1-
,2,4-oxadiazol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene
(Compound 89)
[0352] [step 1] Using 4-chloro-2-propylbenzimidazole (0.124 g,
0.639 mmol) instead of 4-chloro-2-ethylbenzimidazole, and in the
same manner as in Example 87, step 1,
(E)-{2-[1-(4-chloro-2-propylbenzimidazol-1-yl)ethyl]-10,11-dihydro-5H-dib-
enzo[a,d]cyclohepten-5-ylidene}acetonitrile (0.050 g, 19%) was
obtained. [step 2] Using
(E)-{2-[1-(4-chloro-2-propylbenzimidazol-1-yl)ethyl-10,11-dihydro-5H-dibe-
nzo[a,d]cyclohepten-5-ylidene}acetonitrile (0.050 g, 0.110 mmol)
obtained in the above-mentioned step 1 and in the same manner as in
Example 5, the title compound (compound 89) (0.003 g, 5%) was
obtained.
[0353] ESI-MS m/z: 511 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.06 (t, J=7.4 Hz, 3H), 1.78-1.96 (m, 2H), 2.02 (d, J=6.9
Hz, 3H), 2.76-3.07 (m, 2H), 3.08-3.54 (m, 4H), 5.72-5.89 (m, 1H),
6.45-6.58 (m, 1H), 6.78-6.96 (m, 2H), 7.01-7.51 (m, 8H).
Example 90
(E)-N-Phenyl-[2-(2,4-dimethyl-6-phenylbenzimidazol-1-yl)methyl-10,11-dihyd-
ro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetamide (Compound 90)
[0354]
(E)-[2-(2,4-Dimethyl-6-phenylbenzimidazol-1-yl)methyl-10,11-dihydro-
-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetic acid (0.050 g, 0.103
mmol) obtained in Example 55 was dissolved in DMF (1 mL), aniline
(0.018 mL, 0.200 mmol),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.047 g, 0.240 mmol)
and 1-hydroxybenzotriazole (0.032 g, 0.240 mmol) were added, and
the mixture was stirred at room temperature for 15 hr. Saturated
aqueous sodium hydrogen carbonate solution was added to the
mixture, and the precipitated solid was collected by suction
filtration to give the title compound (compound 90) (0.048 g,
83%).
[0355] ESI-MS m/z: 560 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.58 (s, 3H), 2.73 (s, 3H), 2.88-3.30 (m, 4H), 5.30 (s,
2H), 6.31 (s, 1H), 6.73-6.81 (m, 2H), 6.91-7.08 (m, 5H), 7.15-7.44
(m, 11H), 7.53-7.59 (m, 2H).
Example 91
(E)-[2-(2,4-Dimethyl-6-phenylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dib-
enzo[a,d]cyclohepten-5-ylidene]-N-methylacetamide (Compound 91)
[0356] Using methylamine hydrochloride (0.028 g, 0.412 mmol)
instead of aniline, and in the same manner as in Example 90, the
title compound (compound 91) (0.056 g, 54%) was obtained.
[0357] ESI-MS m/z: 498 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.52-2.64 (m, 6H), 2.72 (s, 3H), 2.77-3.26 (m, 4H),
4.98-5.13 (m, 1H), 5.28 (s, 2H), 6.21 (s, 1H), 6.72 (s, 1H),
6.90-6.93 (m, 1H), 7.15-7.45 (m, 10H), 7.51-7.62 (m, 2H).
Example 92
(E)-2-[4-Methyl-6-(5-methyl-1,3-oxazol-2-yl)-2-propylbenzimidazol-1-yl]met-
hyl-5-(1H-tetrazol-5-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-
e (Compound 92)
[0358] [step 1]
4-Methyl-6-(5-methyl-1,3-oxazol-2-yl)-2-propylbenzimidazole (120
mg, 0.47 mmol) obtained in Reference Example A10 was dissolved in
DMF (2.8 mL),
(E)-2-(2-bromomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)a-
cetonitrile (160 mg, 0.49 mmol) obtained in Reference Example B1
and potassium carbonate (325 mg, 2.35 mmol) were added, and the
mixture was stirred at 60.degree. C. for 4 hr. Water was added to
the mixture, and the mixture was extracted with ethyl acetate. The
organic layer was washed with water, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/ethyl
acetate=80/20 to 30/70) to give
(E)-{2-[4-methyl-6-(5-methyl-1,3-oxazol-2-yl)-2-propylbenzimidazol-1-yl]m-
ethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(157 mg, 67%). [step 2] Using
(E)-{2-[4-methyl-6-(5-methyl-1,3-oxazol-2-yl)-2-propylbenzimidazol-1-yl]m-
ethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(50 mg, 0.10 mmol) obtained in step 1 and in the same manner as in
Example 4, the title compound (compound 92) (28 mg, 52%) was
obtained.
[0359] ESI-MS m/z: 542 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.00 (t, J=7.3 Hz, 3H), 1.74-1.89 (m, 2H), 2.37 (d, J=1.0
Hz, 3H), 2.71 (s, 3H), 2.74-2.97 (m, 4H), 3.12-3.38 (m, 2H), 5.34
(s, 2H), 6.71 (s, 1H), 6.74-6.77 (m, 1H), 6.88-6.95 (m, 1H), 7.04
(s, 1H), 7.14 (d, J=7.3 Hz, 1H), 7.27-7.31 (m, 1H), 7.33-7.45 (m,
3H), 7.67 (s, 1H), 7.73 (s, 1H).
Example 93
(E)-2-[4-Methyl-6-(4-methyl-1,3-oxazol-2-yl)-2-propylbenzimidazol-1-yl]met-
hyl-5-(1H-tetrazol-5-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-
e (Compound 93)
[0360] [step 1] Using
(E)-2-(2-bromomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)a-
cetonitrile (56 mg, 0.17 mmol) obtained in Reference Example B1 and
4-methyl-6-(4-methyl-1,3-oxazol-2-yl)-2-propylbenzimidazole (40 mg,
0.16 mmol) obtained in Reference Example A11, step 3, and in the
same manner as in Example 92, step 1,
(E)-{2-[4-methyl-6-(4-methyl-1,3-oxazol-2-yl)-2-propylbenzimidazol-1-yl]m-
ethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(76 mg, 97%) was obtained. [step 2] Using
(E)-{2-[4-methyl-6-(4-methyl-1,3-oxazol-2-yl)-2-propylbenzimidazol-1-yl]m-
ethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(75 mg, 0.15 mmol) obtained in step 1 and in the same manner as in
Example 4, the title compound (compound 93) (21 mg, 26%) was
obtained.
[0361] ESI-MS m/z: 542 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.00 (t, J=7.3 Hz, 3H), 1.74-1.89 (m, 2H), 2.21 (d, J=1.1
Hz, 3H), 2.71 (s, 3H), 2.77-2.85 (m, 2H), 2.85-3.00 (m, 2H),
3.12-3.40 (m, 2H), 5.34 (s, 2H), 6.70 (s, 1H), 6.89-6.95 (m, 1H),
7.05 (s, 1H), 7.14-7.18 (m, 1H), 7.28-7.33 (m, 1H), 7.35-7.46 (m,
4H), 7.69 (s, 1H), 7.76 (s, 1H).
Example 94
(E)-1-(-{2-[4-Methyl-6-(1,3-oxazol-2-yl)-2-propylbenzimidazol-1-yl]methyl--
10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetyl)pyrrolidine-2-ca-
rboxylic acid (Compound 94)
[0362] [step 1] Using
(E)-{2-[4-methyl-6-(1,3-oxazol-2-yl)-2-propylbenzimidazol-1-yl]methyl-10,-
11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (71
mg, 0.15 mmol) obtained in Example 69, step 1 and in the same
manner as in Example 55,
(E)-{2-[4-methyl-6-(1,3-oxazol-2-yl)-2-propylbenzimidazol-1-yl]methyl-
-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetic acid (42
mg, 57%) was obtained. [step 2]
(E)-{2-[4-Methyl-6-(oxazol-2-yl)-2-propylbenzimidazol-1-yl]methyl-10,11-d-
ihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetic acid (125 mg,
0.25 mmol) obtained in step 1 was dissolved in DMF (2.5 mL),
(DL)-methylpyrrolidine-2-carboxylate hydrochloride (82 mg, 0.50
mol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (57 mg, 0.30
mmol), triethylamine (69 .mu.L, 0.50 mmol) and
1-hydroxybenzotriazole (46 mg, 0.30 mmol) were added, and the
mixture was stirred at room temperature for 4 hr. Saturated aqueous
sodium hydrogen carbonate solution (10 mL) was added to the
mixture, and the mixture was extracted with chloroform (70 mL). The
organic layer was washed with brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography
(chloroform/methanol=99/1 to 93/7) to give (DL,E)-methyl
1-{{2-[4-methyl-6-(1,3-oxazol-2-yl)-2-propylbenzimidazol-1-yl]methyl-10,1-
1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetyl}pyrrolidine-2-carbox-
ylate (57 mg, 80%). [step 3] (DL,E)-Methyl
1-{{2-[4-methyl-6-(1,3-oxazol-2-yl)-2-propylbenzimidazol-1-yl]methyl-10,1-
1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetyl}pyrrolidine-2-carbox-
ylate (49 mg, 0.08 mmol) obtained in the above-mentioned step 2 was
dissolved in ethanol (1.2 mL) and water (0.4 mL), lithium hydroxide
monohydrate (17 mg, 0.40 mmol) was added, and the mixture was
stirred at room temperature for 3 hr. 4 mol/L Hydrochloric acid (5
mL) was added to the mixture, and the mixture was extracted with
chloroform (60 mL). The organic layer was dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by C18 reversed-phase column chromatography
(0.05% TFA aqueous solution/acetonitrile=70/30 to 40/60) to give
the title compound (compound 94) (18 mg, 38%).
[0363] ESI-MS m/z: 601 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.96 (t, J=7.3 Hz, 3H), 1.58-2.10 (m, 6H), 2.60 (s, 3H),
2.85 (t, J=7.4 Hz, 2H), 3.15-4.00 (m, 6H), 4.06-4.41 (m, 1H), 5.47
(s, 2H), 6.25 (br s, 1H), 6.83-6.91 (m, 1H), 6.95 (br s, 1H),
6.98-7.06 (m, 1H), 7.08-7.17 (m, 3H), 7.20-7.32 (m, 2H), 7.66 (s,
1H), 7.80 (s, 1H), 7.97 (s, 1H).
Example 95
(E)-2-[N-Methyl
2-({2-[4-methyl-6-(1,3-oxazol-2-yl)-2-propylbenzimidazol-1-yl]methyl-10,1-
1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetamido)]acetic
acid (Compound 95)
[0364] [step 1]
(E)-{2-[4-Methyl-6-(oxazol-2-yl)-2-propylbenzimidazol-1-yl]methyl-10,11-d-
ihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetic acid (190 mg,
0.38 mmol) obtained in Example 94, step 1 was dissolved in DMF (3.8
mL), methyl 2-(methylamino)acetate hydrochloride (125 mg, 0.75
mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (87 mg, 0.45
mmol), triethylamine (105 .mu.L, 0.75 mmol) and
1-hydroxybenzotriazole (69 mg, 0.45 mmol) were added, and the
mixture was stirred at room temperature for 2 hr. Saturated aqueous
sodium hydrogen carbonate solution (10 mL) was added to the
mixture, and the mixture was extracted with ethyl acetate (75 mL).
The organic layer was washed with brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(chloroform/methanol=98/2 to 95/5) to give (E)-methyl
2-{N-methyl-2-{{2-[4-methyl-6-(1,3-oxazol-2-yl)-2-propylbenzimidazol-1-yl-
]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetamido}}acet-
ate (77 mg, 65%). [step 2] Using (E)-methyl
2-[N-methyl-2-({2-[4-methyl-6-(1,3-oxazol-2-yl)-2-propylbenzimidazol-1-yl-
]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetamido)]acet-
ate (65 mg, 0.11 mmol) obtained in step 1 and in the same manner as
in Example 94, step 2, the title compound (compound 95) (22 mg,
35%) was obtained.
[0365] ESI-MS m/z: 575 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.96 (t, J=7.5 Hz, 3H), 1.74-1.85 (m, 2H), 2.59 (s, 3H),
2.72-3.18 (m, 6H), 3.03 (s, 3H), 3.79-4.08 (m, 2H), 5.46 (s, 2H),
6.29 (br s, 1H), 6.83-6.90 (m, 1H), 6.94 (br s, 1H), 6.97-7.06 (m,
1H), 7.07-7.16 (m, 3H), 7.20-7.23 (m, 1H), 7.24-7.32 (m, 1H),
7.60-7.65 (m, 1H), 7.78 (s, 1H), 7.95-7.98 (m, 1H).
Example 96
(E)-8-[(4-Hydroxypropan-2-yl)-2-propylbenzimidazol-1-yl]methyl-11-[1-(5-ox-
o-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxe-
pine (Compound 96)
[0366] [step 1] Using (2-propylbenzimidazol-4-yl)propan-2-ol (190
mg, 0.642 mmol) obtained in Reference Example A15 instead of
2-ethylbenzimidazole, and in the same manner as in Example 26, step
1,
(E)-2-{8-[(4-hydroxypropan-2-yl)-2-propylbenzimidazol-1-yl]methyl-6,11-di-
hydrodibenzo[b,e]oxepin-11-ylidene}propiononitrile (295 mg,
quantitatively) was obtained. [step 2] Using
(E)-2-{8-[(4-hydroxypropan-2-yl)-2-propylbenzimidazol-1-yl]methyl-6,11-di-
hydrodibenzo[b,e]oxepin-11-ylidene}propiononitrile (147 mg, 0.308
mmol) obtained in step 1 and in the same manner as in Example 5,
the title compound (compound 96) (100 mg, 61%) was obtained.
[0367] ESI-MS m/z: 537 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.00 (t, J=7.3 Hz, 3H), 1.72 (s, 6H), 1.84 (m, 2H), 2.28
(s, 3H), 2.76 (t, J=7.3 Hz, 2H), 4.76 (d, J=12.9 Hz, 1H), 5.34 (s,
2H), 5.52 (d, J=12.9 Hz, 1H), 6.80-6.99 (m, 2H), 7.00-7.30 (m,
8H).
Example 97
(E)-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-8-(4-phenyl--
2-propylimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepine
(Compound 97)
[0368] [step 1] Using 4-phenyl-2-propylimidazole (0.091 g, 0.489
mmol) obtained in Reference Example A8 instead of benzimidazole,
and in the same manner as in Example 25, step 1,
(E)-2-{8-(4-phenyl-2-propylimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]o-
xepin-11-ylidene}propiononitrile (0.182 g, 91%) was obtained. [step
2] Using
(E)-2-[8-(4-phenyl-2-propylimidazol-1-yl)methyl-6,11-dihydrodibenzo-
[b,e]oxepin-11-ylidene]propiononitrile (0.182 g, 0.410 mmol)
obtained in step 1 and in the same manner as in Example 5, the
title compound (compound 97) (0.075 g, 36%) was obtained.
[0369] ESI-MS m/z: 505 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.97 (t, J=7.6 Hz, 3H), 1.67-1.87 (m, 2H), 2.26 (s, 3H),
2.63 (t, J=7.6 Hz, 2H), 4.78 (d, J=12.6 Hz, 1H), 5.11 (s, 2H), 5.52
(d, J=12.6 Hz, 1H), 6.81-6.87 (m, 1H), 6.87-6.95 (m, 1H), 6.98-7.11
(m, 4H), 7.11-7.27 (m, 3H), 7.27-7.39 (m, 2H), 7.68-7.79 (m,
2H).
Example 98
(E)-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-8-[2-propyl--
4-(4-pyridyl)imidazol-1-yl]methyl-6,11-dihydrodibenzo[b,e]oxepine
(Compound 98)
[0370] [step 1] Using 2-propyl-4-(4-pyridyl)imidazole (0.044 g,
0.235 mmol) obtained in Reference Example A9 instead of
benzimidazole, and in the same manner as in Example 25, step 1,
(E)-2-{8-[2-propyl-4-(4-pyridyl)imidazol-1-yl]methyl-6,11-dihydrodibenzo[-
b,e]oxepin-11-ylidene}propiononitrile (0.043 g, 40%) was obtained.
[step 2] Using
(E)-2-{8-[2-propyl-4-(4-pyridyl)imidazol-1-yl]methyl-6,11-dihydr-
odibenzo[b,e]oxepin-11-ylidene}propiononitrile (0.043 g, 0.096
mmol) obtained in Example 98, step 1 and in the same manner as in
Example 5, the title compound (compound 98) (0.004 g, 8%) was
obtained.
[0371] ESI-MS m/z: 506 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.93-1.04 (m, 3H), 1.67-1.85 (m, 2H), 2.28-2.37 (m, 3H),
2.55-2.71 (m, 2H), 4.59-4.75 (m, 1H), 5.07-5.16 (m, 2H), 5.38-5.51
(m, 1H), 6.79-6.89 (m, 2H), 6.89-7.02 (m, 1H), 7.07-7.32 (m, 5H),
7.55-7.68 (m, 2H), 8.32-8.45 (m, 2H).
Example 99
(E)-8-(2-Methyl-4-phenylimidazol-1-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,-
4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine
(Compound 99)
[0372] [step 1] Using 4-iodo-2-methylimidazole
(Synthesis-Stuttgart, 1994, 7, 681-682, 0.310 g, 0.149 mmol)
instead of benzimidazole, and in the same manner as in Example 25,
step 1,
(E)-2-[8-(4-iodo-2-methylimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxe-
pin-11-ylidene]propiononitrile (0.300 g, 64%) was obtained. [step
2]
(E)-2-[8-(4-Iodo-2-methylimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxe-
pin-11-ylidene]propiononitrile (0.150 g, 3.21 mmol) obtained in
step 1 was dissolved in DMF (2 mL), phenylboronic acid (0.051 g,
0.417 mmol), tetrakistriphenylphosphine palladium (0.056 g, 0.048
mmol) and sodium carbonate (0.085 g, 0.803 mmol) were added, and
the mixture was heated under reflux for 3 hr. Water was added to
the reaction mixture, and the mixture was extracted three times
with ethyl acetate. The combined organic layers were dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (hexane//ethyl acetate=1/2) to give
(E)-2-[8-(2-iodo-4-phenylimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxe-
pin-11-ylidene]propiononitrile (0.079 g, 58%). [step 3] Using
(E)-2-[8-(2-iodo-4-phenylimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxe-
pin-11-ylidene]propiononitrile (0.079 g, 0.189 mmol) obtained in
step 2 and in the same manner as in Example 5, the title compound
(compound 99) (0.007 g, 18%) was obtained.
[0373] ESI-MS m/z: 477 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.17 (s, 3H), 2.29 (s, 3H), 4.59 (d, J=12.6 Hz, 1H), 5.02
(s, 2H), 5.42 (d, J=12.6 Hz, 1H), 6.78-6.86 (m, 2H), 6.86-6.98 (m,
1H), 7.04-7.15 (m, 2H), 7.16-7.25 (m, 3H), 7.28-7.37 (m, 3H),
7.60-7.69 (m, 2H).
Example 100
(E)-1-{11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihy-
drodibenzo[b,e]oxepin-8-yl}methyl-2-propylbenzimidazole-4-carboxamide
(Compound 100)
[0374] [step 1] Methyl 2-propyl-1H-benzimidazole-4-carboxylate (600
mg, 2.75 mmol) obtained in Reference Example A12 was dissolved in
DMF (3.6 mL),
(E)-2-(8-chloromethyl-6,11-dihydrobenzo[b,e]oxepin-11-ylidene)propio-
nonitrile (853 mg, 2.89 mmol) obtained in Reference Example B5 and
potassium carbonate (1.9 g, 13.8 mmol) were added, and the mixture
was stirred at 60.degree. C. for 4 hr. Water was added to the
mixture, and the mixture was extracted with ethyl acetate. The
organic layer was washed with water, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/ethyl
acetate=80/20 to 30/70) to give (E)-methyl
1-[11-(1-cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl-2-pr-
opylbenzimidazole-4-carboxylate (970 mg, 74%). [step 2] (E)-Methyl
1-[11-(1-cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl-2-pr-
opylbenzimidazole-4-carboxylate (870 mg, 1.82 mmol) obtained in
step 1 was dissolved in ethanol (13 mL) and THF (2.6 mL), 4 mmol/L
aqueous sodium hydroxide solution (8.7 mL) was added, and the
mixture was stirred at 70.degree. C. for 30 min. The mixture was
concentrated under reduced pressure, adjusted to pH 3 by adding 4
mol/L hydrochloric acid under ice-cooling, and the mixture was
stirred for 30 min. The precipitated solid was collected by
filtration to give
(E)-1-[11-(1-cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl--
2-propylbenzimidazole-4-carboxylic acid (785 mg, 93%). [step 3]
(E)-1-[11-(1-Cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl--
2-propylbenzimidazole-4-carboxylic acid (250 mg, 0.54 mmol)
obtained in step 2 was dissolved in THF (2.7 mL),
N,N'-carbonyldiimidazole (114 mg, 0.70 mmol) was added, and the
mixture was stirred at room temperature for 5 hr. Ammonia (25%
aqueous solution, 110 .mu.L, 1.62 mmol) was added to the mixture,
and the mixture was stirred at room temperature for 15 hr. The
mixture was adjusted to pH 6 with 1 mol/L hydrochloric acid, and
the mixture was extracted with ethyl acetate (65 mL). The organic
layer was washed with saturated aqueous sodium hydrogen carbonate
solution, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate=70/30 to 40/60) to give
(E)-1-[11-(1-cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl--
2-propylbenzimidazole-4-carboxamide (249 mg, quantitative). [step
4] Using
(E)-1-[11-(1-cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl--
2-propylbenzimidazole-4-carboxamide (249 mg, 0.54 mmol) obtained in
step 3 and in the same manner as in Example 5, the title compound
(compound 100) (81 mg, 29%) was obtained.
[0375] ESI-MS m/z: 522 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.93 (t, J=7.3 Hz, 3H), 1.66-1.82 (m, 2H), 2.17 (s, 3H),
2.86 (t, J=7.5 Hz, 2H), 4.90 (d, J=12.5 Hz, 1H), 5.46 (d, J=12.5
Hz, 1H), 5.57 (s, 2H), 6.78 (d, J''=8.1 Hz, 1H), 6.93 (t, J=7.3 Hz,
1H), 7.04-7.12 (m, 2H), 7.15-7.33 (m, 4H), 7.64-7.76 (m, 2H), 7.83
(d, J=7.3 Hz, 1H), 9.28 (t, J=3.3 Hz, 1H), 12.15 (br s, 1H).
Example 101
(E)-8-[4-(4-Hydroxypiperidine-1-carbonyl)-2-propylbenzimidazol-1-yl]methyl-
-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodib-
enzo[b,e]oxepine (Compound 101)
[0376] [step 1]
(E)-1-[11-(1-Cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl--
2-propylbenzimidazole-4-carboxylic acid (220 mg, 0.48 mmol)
obtained in Example 100, step 2 was dissolved in DMF (4.0 mL),
4-hydroxypiperidine (96 mg, 0.95 mmol),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (109 mg, 0.57 mmol)
and 1-hydroxybenzotriazole (87 mg, 0.57 mmol) were added, and the
mixture was stirred at room temperature for 15 hr. Saturated
aqueous sodium hydrogen carbonate solution (15 mL) was added to the
mixture, and the precipitated solid was collected by filtration.
The residue was purified by silica gel column chromatography
(chloroform/methanol=99/1 to 93/7) to give
(E)-2-{8-[4-(4-hydroxy-1-piperidinecarbonyl)-2-propylbenzimidazol-1-yl]me-
thyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene}propiononitrile (260
mg, 100%). [step 2] Using
(E)-2-{8-[4-(4-hydroxy-1-piperidinecarbonyl)-2-propylbenzimidazol-1-yl]me-
thyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene}propiononitrile (260
mg, 0.48 mmol) obtained in step 1 and in the same manner as in
Example 5, the title compound (compound 101) (85 mg, 30%) was
obtained.
[0377] ESI-MS m/z: 606 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.89 (t, J=7.3 Hz, 3H), 1.28-1.51 (m, 2H), 1.58-1.75 (m,
3H), 1.76-1.89 (m, 1H), 2.17 (s, 3H), 2.79 (t, J=7.5 Hz, 2H),
2.91-3.05 (m, 1H), 3.19-3.27 (m, 1H), 3.65-3.80 (m, 1H), 4.07-4.21
(m, 1H), 4.75 (d, J=3.7 Hz, 1H), 4.89 (d, J=12.8 Hz, 1H), 5.47 (d,
J=12.8 Hz, 1H), 5.51 (s, 2H), 6.79 (d, J=8.4 Hz, 1H), 6.93 (t,
J=7.1 Hz, 1H), 7.04-7.12 (m, 3H), 7.14-7.27 (m, 4H), 7.49 (d, J=7.7
Hz, 1H), 12.14 (br s, 1H).
Example 102
(E)-N-(2-Hydroxyethyl)
1-{11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydro-
dibenzo[b,e]oxepin-8-yl}methyl-2-propylbenzimidazole-4-carboxamide
(Compound 102)
[0378] [step 1]
(E)-1-[11-(1-Cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl--
2-propylbenzimidazole-4-carboxylic acid (220 mg, 0.48 mmol)
obtained in Example 100, step 2 was dissolved in DMF (4.0 mL),
2-aminoethanol (57 .mu.L, 0.95 mmol),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (109 mg, 0.57 mmol)
and 1-hydroxybenzotriazole (87 mg, 0.57 mmol) were added, and the
mixture was stirred at room temperature for 15 hr. Saturated
aqueous sodium hydrogen carbonate solution (15 mL) was added to the
mixture, and the precipitated solid was collected by filtration.
The residue was purified by silica gel column chromatography
(chloroform/methanol=99/1 to 95/5) to give (E)-N-(2-hydroxyethyl)
1-[11-(1-cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl-2-pr-
opylbenzimidazole-4-carboxamide (241 mg, 99%). [step 2] Using
(E)-N-(2-hydroxyethyl)
1-[11-(1-cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl-2-pr-
opylbenzimidazole-4-carboxamide (240 mg, 0.47 mmol) obtained in
step 1 and in the same manner as in Example 5, the title compound
(compound 102) (70 mg, 26%) was obtained.
[0379] ESI-MS m/z: 566 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.94 (t, J=7.3 Hz, 3H), 1.69-1.87 (m, 2H), 2.17 (s, 3H),
2.85 (t, J=7.4 Hz, 2H), 3.44-3.64 (m, 4H), 4.82 (t, J=5.0 Hz, 1H),
4.89 (d, J=12.9 Hz, 1H), 5.46 (d, J=12.9 Hz, 1H), 5.57 (s, 2H),
6.78 (d, J=8.3 Hz, 1H), 6.93 (t, J=6.9 Hz, 1H), 7.06 (s, 2H),
7.17-7.33 (m, 4H), 7.67 (d, J=7.3 Hz, 1H), 7.84 (d, J=6.9 Hz, 1H),
10.04 (t, J=5.3 Hz, 1H), 12.15 (br s, 1H).
Example 103
(E)-N-{1-{11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-d-
ihydrodibenzo[b,e]oxepin-8-yl}methyl-2-propylbenzimidazol-4-yl}methanesulf-
onamide (Compound 103)
[0380] [step 1]
(E)-1-[11-(1-Cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl--
2-propylbenzimidazole-4-carboxylic acid (220 mg, 0.48 mmol)
obtained in Example 100, step 2 was dissolved in chloroform (9.0
mL), triethylamine (1.3 mL, 9.3 mmol) and diphenylphosphoryl azide
(2.1 mL, 9.3 mmol) were added, and the mixture was stirred at room
temperature for 5 hr. tert-Butanol (9 mL) was added to the mixture,
and the mixture was stirred at 100.degree. C. for 42 hr. Saturated
aqueous sodium hydrogen carbonate solution (20 mL) was added to the
mixture, and the mixture was extracted with chloroform (80 mL). The
organic layer was dried over anhydrous magnesium sulfate, and dried
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate=100/0 to 40/60) to give
(E)-tert-butyl
1-[11-(1-cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl-2-pr-
opylbenzimidazol-4-ylcarbamate (90 mg, 9%). [step 2] (E)-tert-Butyl
1-[11-(1-cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl-2-pr-
opylbenzimidazol-4-ylcarbamate (100 mg, 0.19 mmol) obtained in step
1 was dissolved in dichloromethane (1 mL), trifluoroacetic acid
(0.31 mL) was added dropwise, and the mixture was stirred at room
temperature for 2 hr. Under ice-cooling, saturated aqueous sodium
hydrogen carbonate solution (15 mL) was added to the mixture, and
the mixture was extracted with chloroform (75 mL). The organic
layer was dried over anhydrous magnesium sulfate, and dried under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=70/30 to 20/80) to give
(E)-2-[8-(4-amino-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodiben-
zo[b,e]oxepin-11-ylidene]propiononitrile (40 mg, 49%). [step 3]
(E)-2-[8-(4-Amino-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,-
e]oxepin-11-ylidene]propiononitrile (40 mg, 0.09 mmol) obtained in
step 2 was dissolved in dichloromethane (1.5 mL), pyridine (0.14
mL), dimethylaminopyridine (2 mg, 0.02 mmol) and methanesulfonyl
chloride (7.8 .mu.L, 0.10 mmol) were added, and the mixture was
stirred at room temperature for 4 hr. 2 mmol/L Hydrochloric acid
(10 mL) was added to the mixture, and the mixture was extracted
with chloroform (60 mL). The organic layer was washed with
saturated aqueous sodium hydrogen carbonate solution, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=80/20 to 20/80) to give
(E)-N-{1-[11-(1-cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]meth-
yl-2-propylbenzimidazol-4-yl}methanesulfonamide (47 mg, 100%).
[step 4] Using
(E)-N-{1-[11-(1-cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-y-
l]methyl-2-propylbenzimidazol-4-yl}methanesulfonamide (45 mg, 0.090
mmol) obtained in step 3 and in the same manner as in Example 5,
the title compound (compound 103) (14 mg, 28%) was obtained.
[0381] ESI-MS m/z: 572 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.97 (t, J=7.4 Hz, 3H), 1.73-1.90 (m, 2H), 2.30 (s, 3H),
2.85 (t, J=7.6 Hz, 2H), 3.11 (s, 3H), 4.76 (d, J=12.9 Hz, 1H), 5.38
(s, 2H), 5.53 (d, J=12.9 Hz, 1H), 6.80-6.86 (m, 1H), 6.90-7.00 (m,
2H), 7.02-7.08 (m, 2H), 7.10-7.24 (m, 4H), 7.43 (d, J=7.3 Hz,
1H).
Example 104
(E)-8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-11-(5-oxo-4,5-dihydro-1,2-
,4-oxadiazol-3-yl)methylene-6,11-dihydrodibenzo[b,e]oxepine
(Compound 104)
[0382] [step 1] Using
(E)-2-(8-bromomethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)acetonitri-
le (1.5 g, 4.6 mmol) obtained in Reference Example B13 and
4-methyl-2-propylbenzimidazole (EP400835; 842 mg, 4.83 mmol) and in
the same manner as in Example 92, step 1,
(E)-2-{8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene}acetonitrile (1.47 g, 76%) was obtained. [step
2]
(E)-2-{8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene}acetonitrile (150 mg, 0.34 mmol) obtained in
step 1 was dissolved in ethanol (1.8 mL), hydroxylamine (50%
aqueous solution, 1.1 mL, 17.9 mmol) was added, and the mixture was
stirred under reflux for 18 hr. Water was added to the mixture, and
the mixture was extracted with chloroform. The organic layer was
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The obtained residue was dissolved in
dichloromethane (1.8 mL), triethylamine (75 .mu.L, 0.54 mmol) and
ethyl chlorocarbonate (51 .mu.L, 0.54 mmol) were added at 0.degree.
C., and the mixture was stirred at room temperature for 30 min.
Water was added to the mixture, and the mixture was extracted with
chloroform. The organic layer was dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The obtained
residue was dissolved in toluene (0.9 mL) and THF (0.9 mL),
potassium tert-butoxide (80 mg, 0.72 mmol) was added, and the
mixture was stirred at room temperature for 20 min. 5% Aqueous
citric acid solution was added to the mixture, and the mixture was
extracted with chloroform. The organic layer was dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=70/30 to 10/90) to give the
title compound (compound 104) (119 mg, 70%).
[0383] ESI-MS m/z: 479 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.93 (t, J=7.3 Hz, 3H), 1.64-1.81 (m, 2H), 2.52 (s, 3H),
2.81 (t, J=7.7 Hz, 2H), 4.91-5.39 (m, 2H), 5.50 (s, 2H), 6.57 (s,
1H), 6.79 (d, J=8.4 Hz, 1H), 6.91-7.11 (m, 4H), 7.18-7.32 (m, 4H),
7.39-7.45 (m, 1H).
Example 105
(E)-N-{2-[8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo-
[b,e]oxepin-11-ylidene]acetyl}methanesulfonamide (Compound 105)
[0384] [step 1] Using
(E)-2-[8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene]acetonitrile (800 mg, 1.91 mmol) obtained in
Example 104, step 1 and in the same manner as in Example 55,
(E)-2-[8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene]acetic acid (838 mg, 100%) was obtained. [step
2] Using
(E)-2-[8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodib-
enzo[b,e]oxepin-11-ylidene]acetic acid (250 mg, 0.57 mmol) obtained
in step 1 and in the same manner as in Example 12, the title
compound (compound 105) (125 mg, 43%) was obtained.
[0385] ESI-MS m/z: 516 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.01 (t, J=7.3 Hz, 3H), 1.73-1.90 (m, 2H), 2.70 (s, 3H),
2.85 (t, J=7.9 Hz, 2H), 3.20 (s, 3H), 4.80-5.30 (m, 2H), 5.37 (s,
2H), 6.30 (s, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H),
6.97-7.15 (m, 5H), 7.21-7.35 (m, 3H).
Example 106
(E)-8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-11-(2-oxo-2,3-dihydro-1,3-
,4-oxadiazol-5-yl)methylene-6,11-dihydrodibenzo[b,e]oxepine
(Compound 106)
[0386] [step 1]
(E)-2-[8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene]acetic acid (300 mg, 0.68 mmol) obtained in
Example 105, step 1 was dissolved in THF (6.8 ml) and
dichloromethane (6 mL), N,N'-carbonyldiimidazole (444 mg, 2.74
mmol) was added, and the mixture was stirred at room temperature
for 4 hr. To the mixture was added hydrazine monohydrate (0.33 mL,
6.84 mmol), and the mixture was stirred at room temperature for 5
hr. Water was added to the mixture, and the mixture was extracted
with chloroform (70 mL). The organic layer was dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(chloroform/methanol=100/0 to 85/15) to give
(E)-2-[8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene]acetohydrazide (309 mg, 100%). [step 2]
(E)-2-[8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene]acetohydrazide (118 mg, 0.25 mmol) obtained in
step 1 was dissolved in dichloromethane (2.5 ml),
N,N'-carbonyldiimidazole (120 mg, 0.74 mmol) was added, and the
mixture was stirred at room temperature for 3 hr. Water was added
to the mixture, and the mixture was extracted with ethyl acetate
(80 mL). The organic layer was dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography
(chloroform/methanol=100/0 to 93/7) to give the title compound
(compound 106) (30 mg, 25%).
[0387] ESI-MS m/z: 479 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.93 (t, J=7.3 Hz, 3H), 1.67-1.81 (m, 2H), 2.52 (s, 3H),
2.81 (t, J=7.7 Hz, 2H), 4.72-5.10 (m, 1H), 5.21-5.64 (m, 1H), 5.52
(s, 2H), 6.57 (s, 1H), 6.76 (dd, J=1.1, 8.1 Hz, 1H), 6.91-7.07 (m,
4H), 7.20-7.28 (m, 3H), 7.33 (d, J=7.7 Hz, 1H), 7.42 (dd, J=1.6,
7.9 Hz, 1H), 12.42 (br s, 1H).
Example 107
(E)-8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-11-(1,3,4-oxadiazol-2-yl)-
methylene-6,11-dihydrodibenzo[b,e]oxepine (Compound 107)
[0388] To
(E)-2-[8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydro-
dibenzo[b,e]oxepin-11-ylidene]acetohydrazide (118 mg, 0.25 mmol)
obtained in Example 106, step 1 was added triethoxymethane (2.1
mL), and the mixture was stirred at 120.degree. C. for 5 hr. The
mixture was concentrated under reduced pressure, and the residue
was purified by silica gel column chromatography (hexane/ethyl
acetate=70/30 to 10/90) to give the title compound (compound 107)
(18 mg, 16%).
[0389] ESI-MS m/z: 463 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.01 (t, J=7.3 Hz, 3H), 1.74-1.90 (m, 2H), 2.70 (s, 3H),
2.81-2.91 (m, 2H), 4.51-5.58 (m, 2H), 5.37 (s, 2H), 6.83 (dd,
J=1.0, 8.3 Hz, 1H), 6.93-7.14 (m, 7H), 7.20-7.26 (m, 2H), 7.43 (dd,
J=1.7, 7.9 Hz, 1H), 8.12 (d, J=0.7 Hz, 1H).
Example 108
(E)-8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-11-(1,2,4-oxadiazol-3-yl)-
methylene-6,11-dihydrodibenzo[b,e]oxepine (Compound 108)
[0390] [step 1]
(E)-2-{8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene}acetonitrile (310 mg, 0.74 mmol) obtained in
Example 104, step 1 was dissolved in ethanol (3.7 mL),
hydroxylamine (50% aqueous solution, 2.3 mL, 36.95 mmol) was added,
and the mixture was stirred under reflux for 16 hr. Water was added
to the mixture, and the precipitated solid was collected by
filtration to give
(E)-2-[8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene]acetaldoxime (304 mg, 91%). [step 2] Using
(E)-2-[8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene]acetaldoxime (150 mg, 0.33 mmol) obtained in
step 1 and in the same manner as in Example 107, the title compound
(compound 108) (7.1 mg, 5%) was obtained.
[0391] ESI-MS m/z: 463 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.00 (t, J=7.4 Hz, 3H), 1.71-1.89 (m, 2H), 2.69 (s, 3H),
2.85 (t, J=7.9 Hz, 2H), 4.50-5.57 (m, 2H), 5.36 (s, 2H), 6.82 (dd,
J=1.2, 8.4 Hz, 1H), 6.89-7.00 (m, 3H), 7.01-7.25 (m, 6H), 7.46 (dd,
J=1.7, 7.9 Hz, 1H), 8.48 (s, 1H).
Example 109
(E)-8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-11-(5-trifluoromethyl-1,2-
,4-oxadiazol-3-yl)methylene-6,11-dihydrodibenzo[b,e]oxepine
(Compound 109)
[0392]
(E)-2-[8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodib-
enzo[b,e]oxepin-11-ylidene]acetaldoxime (150 mg, 0.33 mmol)
obtained in Example 108, step 1 was dissolved in dichloromethane
(3.3 mL), bistrifluoroacetic acid anhydride (0.14 mL, 0.99 mmol)
and triethylamine (0.14 mL, 0.99 mmol) were added, and the mixture
was stirred at room temperature for 17 hr. To the mixture was added
saturated aqueous sodium hydrogen carbonate solution (15 mL), and
the mixture was extracted with ethyl acetate (75 mL). The organic
layer was dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate=70/30 to 40/60) to give
the title compound (compound 109) (75 mg, 43%).
[0393] ESI-MS m/z: 531 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.00 (t, J=7.4 Hz, 3H), 1.70-1.89 (m, 2H), 2.70 (s, 3H),
2.85 (t, J=7.9 Hz, 2H), 4.55-5.69 (m, 2H), 5.37 (s, 2H), 6.79-6.86
(m, 1H), 6.89 (s, 1H), 6.91-7.11 (m, 6H), 7.16 (d, J=7.9 Hz, 1H),
7.21-7.30 (m, 1H), 7.44 (dd, J=1.3, 7.9 Hz, 1H).
Example 110
(E)-11-Cyclopropyl(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methylene-8-(2-p-
ropylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepine
(Compound 110)
[0394] [step 1]
(E)-2-(8-Hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)cyclopro-
pylacetonitrile (0.200 g, 0.661 mmol) obtained in Reference Example
B9 was dissolved in THF (2 mL), 2,6-lutidine (0.460 mL, 3.96 mmol),
lithium bromide (0.344 g, 3.96 mmol) and methanesulfonic anhydride
(0.288 g, 1.65 mmol) were added, and the mixture was stirred at
room temperature for 16 hr. Water was added to the mixture and the
mixture was extracted 3 times with ethyl acetate. The combined
organic layer was dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to give a residue.
[0395] 2-Propylbenzimidazole (0.091 g, 0.571 mmol) was dissolved in
DMF (2 mL), potassium carbonate (0.375 g, 2.72 mmol) was added and
the mixture was stirred for 15 min. To this mixture was added the
residue obtained above, and the mixture was stirred at 60.degree.
C. for 2 hr. Water was added to the mixture and the mixture was
extracted 3 times with ethyl acetate. The combined organic layer
was dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane/ethyl acetate=1/2) to give
(E)-2-[8-(2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-
-11-ylidene]cyclopropylacetonitrile (0.201 g, 64%).
[step 2] Using
(E)-2-[8-(2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-
-11-ylidene]cyclopropylacetonitrile (0.200 g, 0.449 mmol) obtained
in step 1 and in the same manner as in Example 5, the title
compound (compound 110) (0.036 g, 15%) was obtained.
[0396] ESI-MS m/z: 505 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.64-0.84 (m, 2H), 0.81-1.06 (m, 5H), 1.55-1.79 (m, 2H),
1.91-2.10 (m, 1H), 2.72-2.88 (m, 2H), 4.87 (d, J=12.6 Hz, 1H),
5.45-5.63 (m, 3H), 6.79 (d, J=8.2 Hz, 1H), 6.88-7.20 (m, 1H),
6.99-7.13 (m, 2H), 7.13-7.29 (m, 4H), 7.34-7.54 (m, 2H), 7.54-7.68
(m, 1H), 12.18 (br s, 1H).
Example 111
(E)-8-(4-Chloro-2-propylbenzimidazol-1-yl)methyl-11-cyclopropyl(5-oxo-4,5--
dihydro-1,2,4-oxadiazol-3-yl)methylene-6,11-dihydrodibenzo[b,e]oxepine
(Compound 111)
[0397] [step 1] Using 4-chloro-2-propylbenzimidazole (0.034 g,
0.175 mmol) instead of 2-propylbenzimidazole, and in the same
manner as in Example 110, step 1,
(E)-2-[8-(4-chloro-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene]cyclopropylacetonitrile (0.072 g, 72%) was
obtained. [step 2] Using
(E)-2-[8-(4-chloro-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene]cyclopropylacetonitrile (0.070 g, 0.146 mmol)
obtained in step 1 and in the same manner as in Example 5, the
title compound (compound 111) (0.020 g, 25%) was obtained.
[0398] ESI-MS m/z: 539 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.46-0.64 (m, 1H), 0.72-0.87 (m, 1H), 0.87-1.08 (m, 5H),
1.54-1.96 (m, 2H), 2.02-2.21 (m, 1H), 2.35-2.77 (m, 2H), 4.19 (d,
J=13.2 Hz, 1H), 5.20-5.46 (m, 3H), 6.48-6.56 (m, 1H), 6.72-6.83 (m,
1H), 6.89-7.02 (m, 2H), 7.03-7.39 (m, 5H), 7.48-7.59 (m, 1H).
Example 112
(E)-8-(4-Chloro-2-cyclopropylbenzimidazol-1-yl)methyl-11-cyclopropyl(5-oxo-
-4,5-dihydro-1,2,4-oxadiazol-3-yl)methylene-6,11-dihydrodibenzo[b,e]oxepin-
e (Compound 112)
[0399] [step 1] Using 4-chloro-2-cyclopropylbenzimidazole
(WO2008096829, 0.034 g, 0.175 mmol) instead of
2-propylbenzimidazole, and in the same manner as in Example 110,
step 1,
(E)-2-{8-(4-chloro-2-cyclopropylbenzimidazol-1-yl)methyl-6,11-dihydrodibe-
nzo[b,e]oxepin-11-ylidene}cyclopropylacetonitrile (0.080 g, 80%)
was obtained. [step 2] Using
(E)-2-[8-(4-chloro-2-cyclopropylbenzimidazol-1-yl)methyl-6,11-dihydrodibe-
nzo[b,e]oxepin-11-ylidene]cyclopropylacetonitrile (0.078 g, 0.163
mmol) obtained in step 1 and in the same manner as in Example 5,
the title compound (compound 112) (0.010 g, 15%) was obtained.
[0400] ESI-MS m/z: 537 (M+H).sup.+; .sup.1H-NMR(CDCl.sub.3,
.delta.): 0.82-1.06 (m, 4H), 1.09-1.31 (m, 4H), 1.78-1.93 (m, 1H),
1.98-2.14 (m, 1H), 4.63 (d, J=12.9 Hz, 1H), 5.39-5.48 (m, 2H), 5.57
(d, J=12.9 Hz, 1H), 6.77-6.86 (m, 1H), 6.86-7.07 (m, 3H), 7.11-7.34
(m, 5H), 7.45-7.52 (m, 1H).
Example 113
(E)-8-[2-(Methoxymethyl)benzimidazol-1-yl]methyl-11-cyclopropyl(5-oxo-4,5--
dihydro-1,2,4-oxadiazol-3-yl)methylene-6,11-dihydrodibenzo[b,e]oxepine
(Compound 113)
[0401] [step 1] Using
(E)-2-(8-hydroxymethyl-6,11-dihydrobenzo[b,e]oxepin-11-ylidene)cyclopropy-
lacetonitrile (170 mg, 0.56 mmol) obtained in Reference Example B9,
step 3 and in the same manner as in Reference Example B1,
(E)-2-(8-bromomethyl-6,11-dihydrobenzo[b,e]oxepin-11-ylidene)cyclopropyla-
cetonitrile (169 mg, 83%) was obtained. [step 2] Using
(E)-2-(8-bromomethyl-6,11-dihydrobenzo[b,e]oxepin-11-ylidene)cyclopropyla-
cetonitrile (75 mg, 0.21 mmol) obtained in step 1 and
2-methoxymethylbenzimidazole (32 mg, 0.20 mmol) obtained in
Reference Example A13, and in the same manner as in Example 92,
step 1,
(E)-2-{8-[2-(methoxymethyl)benzimidazol-1-yl]methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene}cyclopropylacetonitrile (66 mg, 75%) was
obtained. [step 3] Using
(E)-2-[8-(2-methoxymethylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e-
]oxepin-11-ylidene]cyclopropylacetonitrile (65 mg, 0.15 mmol)
obtained in step 2 and in the same manner as in Example 5, the
title compound (compound 113) (8 mg, 11%) was obtained.
[0402] ESI-MS m/z: 507 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.30-0.43 (m, 1H), 0.66-0.81 (m, 2H), 0.87-1.00 (m, 1H),
1.95-2.06 (m, 1H), 3.24 (d, J=1.0 Hz, 3H), 4.65 (s, 2H), 4.86 (d,
J=12.6 Hz, 1H), 5.46-5.55 (m, 3H), 6.79 (d, J=8.3 Hz, 1H),
6.90-6.99 (m, 1H), 7.01-7.06 (m, 1H), 7.09-7.28 (m, 5H), 7.34-7.45
(m, 2H), 7.60-7.68 (m, 1H), 12.18 (s, 1H).
Example 114
(E)-8-(4-Chloro-2-methoxymethylbenzimidazol-1-yl)methyl-11-cyclopropyl(5-o-
xo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methylene-6,11-dihydrodibenzo[b,e]oxep-
ine (Compound 114)
[0403] [step 1] Using
(E)-2-(8-bromomethyl-6,11-dihydrobenzo[b,e]oxepin-11-ylidene)cyclopropyla-
cetonitrile (75 mg, 0.20 mmol) obtained in Example 113, step 1 and
4-chloro-2-methoxymethylbenzimidazole (38 mg, 0.19 mmol) obtained
in Reference Example A14, and in the same manner as in Example 92,
step 1,
(E)-2-[8-(4-chloro-2-methoxymethylbenzimidazol-1-yl)methyl-6,11-dihydrodi-
benzo[b,e]oxepin-11-ylidene]cyclopropylacetonitrile (76 mg, 82%)
was obtained. [step 2] Using
(E)-2-[8-(4-chloro-2-methoxymethylbenzimidazol-1-yl)methyl-6,11-dihydrodi-
benzo[b,e]oxepin-11-ylidene]cyclopropylacetonitrile (75 mg, 0.16
mmol) obtained in step 1 and in the same manner as in Example 5,
the title compound (compound 114) (40 mg, 48%) was obtained.
[0404] ESI-MS m/z: 541 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.30-0.42 (m, 1H), 0.65-0.80 (m, 2H), 0.88-0.99 (m, 1H),
1.93-2.06 (m, 1H), 3.24 (s, 3H), 4.69 (s, 2H), 4.87 (d, J=12.9 Hz,
1H), 5.50 (d, J=12.9 Hz, 1H), 5.54 (s, 2H), 6.76-6.82 (m, 1H),
6.90-6.98 (m, 1H), 7.01-7.06 (m, 1H), 7.10-7.31 (m, 5H), 7.34-7.39
(m, 1H), 7.42 (dd, J=1.5, 7.8 Hz, 1H), 12.17 (s, 1H).
Example 115
(E)-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)butylidene]-8-(2-propylb-
enzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepine (Compound
115)
[0405] [step 1]
(E)-2-(2-Hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridine)pentanenit-
rile (0.370 g, 1.21 mmol) obtained in Reference. Example B11 was
dissolved in THF (6 mL), 2,6-lutidine (0.840 mL, 7.28 mmol),
lithium bromide (0.630 g, 7.28 mmol) and, methanesulfonic anhydride
(0.527 g, 3.03 mmol) were added, and the mixture was stirred at
room temperature for 16 hr. Water was added to the mixture and the
mixture was extracted 3 times with ethyl acetate. The combined
organic layer was dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to give a residue.
[0406] 2-Propylbenzimidazole (0.084 g, 0.526 mmol) was dissolved in
DMF (2 mL), potassium carbonate (0.330 g, 2.39 mmol) was added and
the mixture was stirred for 15 min. To this mixture was added the
residue obtained above, and the mixture was stirred at 60.degree.
C. for 2 hr. Water was added to the mixture and the mixture was
extracted 3 times with ethyl acetate. The combined organic layer
was dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane/ethyl acetate=1/2) to give
(E)-2-{8-(2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-
-11-ylidene}pentanenitrile (0.110 g, 35%).
[step 2] Using
(E)-2-[8-(2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-
-11-ylidene]pentanenitrile (0.110 g, 0.246 mmol) obtained in step 1
and in the same manner as in Example 5, the title compound
(compound 115) (0.026 g, 20%) was obtained.
[0407] ESI-MS m/z: 507 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.81-0.99 (m, 6H), 1.42-1.61 (m, 2H), 1.66-1.88 (m, 2H),
2.51-2.97 (m, 4H), 4.68 (d, J=13.0 Hz, 1H), 5.36 (s, 2H), 5.56 (d,
J=13.0 Hz, 1H), 6.78-6.87 (m, 1H), 6.87-7.02 (m, 3H), 7.04-7.38 (m,
6H), 7.72-7.84 (m, 1H), 12.18 (s, 1H).
Example 116
(E)-2-Fluoro-8-(2-propylbenzimidazol-1-yl)methyl-11-[1-(5-oxo-4,5-dihydro--
1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine
(Compound 116)
[0408] [step 1]
(E)-2-(2-Fluoro-8-hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene-
)propiononitrile (0.115 g, 0.299 mmol) obtained in Reference
Example B12 was dissolved in THF (1.5 mL), 2,6-lutidine (0.21 mL,
1.79 mmol), lithium bromide (0.156 g, 1.79 mmol) and
methanesulfonic anhydride (0.130 g, 0.747 mmol) were added, and the
mixture was stirred at room temperature for 16 hr. Water was added
to the mixture and the mixture was extracted 3 times with ethyl
acetate. The combined organic layer was dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure to give
a residue.
[0409] 2-Propylbenzimidazole (0.032 g, 0.199 mmol) was dissolved in
DMF (1.5 mL), potassium carbonate (0.125 g, 907 mmol) was added and
the mixture was stirred for 15 min. To this mixture was added the
residue obtained above, and the mixture was stirred at 60.degree.
C. for 2 hr. Water was added to the mixture and the mixture was
extracted 3 times with ethyl acetate. The combined organic layer
was dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane/ethyl acetate=1/1) to give
(E)-2-[2-fluoro-8-(2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene]propiononitrile (0.063 g, 48%).
[step 2] Using
(E)-2-[2-fluoro-8-(2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene]propiononitrile (0.063 g, 0.127 mmol) obtained
in step 1 and in the same manner as in Example 5, the title
compound (compound 116) (0.016 g, 25%) was obtained.
[0410] ESI-MS m/z: 497 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.96 (t, J=7.4 Hz, 3H), 1.73-1.91 (m, 2H), 2.31 (s, 3H),
2.72-2.82 (m, 2H), 4.52-4.66 (d, J=12.8 Hz, 1H), 5.28-5.42 (m, 3H),
6.71-6.97 (m, 4H), 6.97-7.06 (m, 1H), 7.08-7.25 (m, 5H), 7.58-7.73
(m, 1H).
Example 117
(E)-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-2-(2-propylbe-
nzimidazol-1-yl)methyl-5,11-dihydrobenzooxepino[3,4-b]pyridine
(Compound 117)
[0411] [step 1]
(E)-2-(2-Hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridine)propiononi-
trile (0.190 g, 0.683 mmol) obtained in Reference Example B10 was
dissolved in THF (3 mL), 2,6-lutidine (0.480 mL, 4.16 mmol),
lithium bromide (0.360 g, 4.16 mmol) and methanesulfonic anhydride
(0.297 g, 1.71 mmol) were added, and the mixture was stirred at
room temperature for 16 hr. Water was added to the mixture and the
mixture was extracted 3 times with ethyl acetate. The combined
organic layer was dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to give a residue.
[0412] 2-Propylbenzimidazole (0.093 g, 0.581 mmol) was dissolved in
DMF (2 mid), potassium carbonate (0.364 g, 2.64 mmol) was added and
the mixture was stirred for 15 min. To this mixture was added the
residue obtained above, and the mixture was stirred at 60.degree.
C. for 2 hr. Water was added to the mixture and the mixture was
extracted 3 times with ethyl acetate. The combined organic layer
was dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane/ethyl acetate=4/1) to give
(E)-2-[2-(2-propylbenzimidazol-1-yl)methyl-5,11-dihydrobenzooxepino[3,4-b-
]pyridin-5-ylidene]propiononitrile (0.180 g, 63%).
[step 2] Using
(E)-2-[2-(2-propylbenzimidazol-1-yl)methyl-5,11-dihydrobenzooxepino[3,4-b-
]pyridin-5-ylidene]propiononitrile (0.120 g, 0.286 mmol) obtained
in step 1 and in the same manner as in Example 5, the title
compound (compound 117) (0.085 g, 62%) was obtained.
[0413] ESI-MS m/z: 480 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.88 (t, J=7.6 Hz, 3H), 1.64-1.86 (m, 2H), 2.21 (s, 3H),
2.74 (t, J=7.6 Hz, 2H), 4.76 (d, J=14.4 Hz, 1H), 5.12-5.38 (m, 3H),
6.76 (d, J=8.0 Hz, 1H), 6.88-7.05 (m, 2H), 7.09-7.32 (m, 5H),
7.43-7.57 (m, 2H), 11.19 (br s, 1H).
Example 118
(E)-2-(2-Propylbenzimidazol-1-yl)methyl-5-[1-(1H-tetrazol-5-yl)ethylidene]-
-5,11-dihydrobenzooxepino[3,4-b]pyridine (Compound 118)
[0414] Using
(E)-2-[2-(2-propylbenzimidazol-1-yl)methyl-5,11-dihydrobenzooxepino[3,4-b-
]pyridin-5-ylidene]propiononitrile (0.050 g, 0.119 mmol) obtained
in Example 117, step 1 and in the same manner as in Example 4, the
title compound (compound 118) (0.005 g, 9%) was obtained.
[0415] ESI-MS m/z: 464 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.94 (t, J=7.6 Hz, 3H), 1.62-1.84 (m, 2H), 2.23 (s, 3H),
2.85 (t, J=7.6 Hz, 2H), 4.86 (d, J=13.5 Hz, 1H), 5.51 (s, 2H), 5.66
(d, J=13.5 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.93-6.98 (m, 1H),
6.99-7.09 (m, 1H), 7.09-7.20 (m, 3H), 7.24-7.36 (m, 2H), 7.38-7.50
(m, 1H), 7.50-7.60 (m, 1H).
Example 119
(E)-2-(7-Chloro-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-5-[1-(5-
-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-5,11-dihydrobenzooxepino-
[3,4-b]pyridine (Compound 119)
[0416] [step 1] Using
7-chloro-2-cyclopropyl-3H-imidazo[4,5-b]pyridine (0.095 g, 0.484
mmol) instead of 2-propylbenzimidazole, and in the same manner as
in Example 117, step 1,
(E)-2-[2-(4-chloro-2-cyclopropylbenzimidazol-1-yl)methyl-5,11-dihydrobenz-
ooxepino[3,4-b]pyridin-5-ylidene]propiononitrile (0.117 g, 40%) was
obtained. [step 2] Using
(E)-2-[2-(7-chloro-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-5,1-
1-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene]propiononitrile
(0.117 g, 0.259 mmol) obtained in Example 119, step 1 and in the
same manner as in Example 5, the title compound (compound 119)
(0.076 g, 57%) was obtained.
[0417] ESI-MS m/z: 513 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.95-1.17 (m, 2H), 1.18-1.34 (m, 2H), 1.94-2.13 (m, 1H),
2.21 (s, 3H), 4.89 (d, (7=15.0 Hz, 1H), 5.40 (d, J=15.0 Hz, 1H),
5.58 (s, 2H), 6.90 (d, J=8.0 Hz, 1H), 7.00-7.12 (m, 2H), 7.12-7.23
(m, 2H), 7.23-7.38 (m, 1H), 7.47 (d, J=8.0 Hz, 1H), 8.04 (d, J=5.5
Hz, 1H), 9.71 (br s, 1H).
Example 120
(E)-2-(4-Chloro-2-cyclopropylbenzimidazol-1-yl)methyl-5-[1-(5-oxo-4,5-dihy-
dro-1,2,4-oxadiazol-3-yl)ethylidene]-5,11-dihydrobenzooxepino[3,4-b]pyridi-
ne (Compound 120)
[0418] [step 1] Using 4-chloro-2-cyclopropylbenzimidazole (0.095 g,
0.484 mmol) instead of 2-propylbenzimidazole and in the same manner
as in Example 117, step 1,
(E)-2-{2-(4-chloro-2-cyclopropylbenzimidazol-1-yl)methyl-5,11-dihydrobenz-
ooxepino[3,4-b]pyridin-5-ylidene}propiononitrile (0.147 g, 50%) was
obtained. [step 2] Using
(E)-2-[2-(4-chloro-2-cyclopropylbenzimidazol-1-yl)methyl-5,11-dihydrobenz-
ooxepino[3,4-b]pyridin-5-ylidene]propiononitrile (0.147 g, 0.325
mmol) obtained in step 1 and in the same manner as in Example 5,
the title compound (compound 120) (0.014 g, 8%) was obtained.
[0419] ESI-MS m/z: 512 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.89-1.08 (m, 2H), 1.17-1.34 (m, 2H), 1.86-2.01 (m, 1H),
2.22 (s, 3H), 4.93 (d, J=14.8 Hz, 1H), 5.39-5.55 (m, 3H), 6.75 (d,
J=8.0 Hz, 1H), 6.99-7.38 (m, 7H), 7.45 (d, J=8.0 Hz, 1H).
Example 121
(Z)-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-2-(2-propylbe-
nzimidazol-1-yl)methyl-5,11-dihydrobenzooxepino[3,4-b]pyridine
(Compound 121)
[0420] [step 1] Propyl
(Z)-5-(1-cyanoethylidene)-5,11-dihydrobenzooxepino[3,4-b]pyridine-2-carbo-
xylate (0.189 g, 0.565 mmol) obtained in Reference Example B10,
step 3 was dissolved in THF (2 mL), lithium borohydride (0.062 g,
2.82 mmol) was added and the mixture was stirred at 60.degree. C.
for 3 hr. To the reaction mixture was added dropwise 1 mol/L
hydrochloric acid under ice-cooling, and the mixture was extracted
3 times with ethyl acetate. The combined organic layer was dried
over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (hexane/ethyl acetate=1/3) to give
(Z)-2-(2-hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridine)pr-
opiononitrile (0.111 g, 71%). [step 2]
(Z)-2-(2-Hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridine)propiononi-
trile (0.111 g, 0.396 mmol) obtained in step 1 was dissolved in THF
(2 mL), 2,6-lutidine (0.276 mL, 2.37 mmol), lithium bromide (0.206
g, 2.37 mmol) and methanesulfonic anhydride (0.172 g, 0.989 mmol)
were added and the mixture was stirred at room temperature for 16
hr. Water was added to the mixture and the mixture was extracted 3
times with ethyl acetate. The combined organic layer was dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure to give a residue.
[0421] 2-Propylbenzimidazole (0.053 g, 0.333 mmol) was dissolved in
DMF (2 mL), potassium carbonate (0.218 g, 1.58 mmol) was added and
the mixture was stirred for 15 min. To this mixture was added the
residue obtained above, and the mixture was stirred at 60.degree.
C. for 2 hr. Water was added to the mixture and the mixture was
extracted 3 times with ethyl acetate. The combined organic layer
was dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane/ethyl acetate=1/3) to give
(Z)-2-[2-(2-propylbenzimidazol-1-yl)methyl-5,11-dihydrobenzooxepino[3,4-b-
]pyridine]propiononitrile (0.094 g, 56%).
[step 3] Using
(Z)-2-[2-(2-propylbenzimidazol-1-yl)methyl-5,11-dihydrobenzooxepino[3,4-b-
]pyridine]propiononitrile (0.090 g, 0.214 mmol) obtained in step 2
and in the same manner as in Example 5, the title compound
(compound 121) (0.026 g, 25%) was obtained.
[0422] ESI-MS m/z: 480 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.95 (t, (7=7.6 Hz, 3H), 1.67-1.86 (m, 2H), 1.96 (s, 3H),
2.90 (t, J=7.6 Hz, 2H), 4.85 (d, J=12.6 Hz, 1H), 5.60 (s, 2H), 5.76
(d, J=12.6 Hz, 1H), 6.78-6.90 (m, 2H), 6.92-7.03 (m, 1H), 7.07-7.31
(m, 4H), 7.42-7.53 (m, 1H), 7.53-7.65 (m, 1H), 7.82 (d, J=7.8 Hz,
1H).
Example 122
(Z)-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-8-(2-propylbe-
nzimidazol-1-yl)methyl-5,11-dihydrobenzooxepino[3,4-b]pyridine
(Compound 122)
[0423] [step 1] Using
(Z)-2-(8-chloromethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)pr-
opiononitrile (0.054 g, 0.182 mmol) obtained in Reference Example
B14 and in the same manner as in Example 1,
(Z)-2-[8-(2-propylbenzimidazol-1-yl)methyl-5,11-dihydrobenzooxepino[3,4-b-
]pyridin-5-ylidene]propiononitrile (0.054 g, 70%) was obtained.
[step 2] Using
(Z)-2-[8-(2-propylbenzimidazol-1-yl)methyl-5,11-dihydrobenzooxepino-
[3,4-b]pyridin-5-ylidene]propiononitrile (0.036 g, 0.075 mmol)
obtained in step 1 and in the same manner as in Example 5, the
title compound (compound 122) (0.016 g, 45%) was obtained.
[0424] ESI-MS m/z: 480 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.94 (t, J=7.3 Hz, 3H), 1.79 (m, 2H), 2.17 (s, 3H), 2.75
(m, 2H), 4.71 (d, J=13.1 Hz, 1H), 5.25 (s, 2H), 5.39 (d, J=13.1 Hz,
1H), 6.45 (s, 1H), 6.68 (d, J=7.9 Hz, 1H), 7.10 (t, J=7.9 Hz, 1H),
7.15-7.39 (m, 4H), 7.58-7.73 (m, 2H), 8.54 (m, 1H).
Example 123
(Z)-8-(2-Propylbenzimidazol-1-yl)methyl-5-(1H-tetrazol-5-yl)methylene-5,11-
-dihydrobenzooxepino[3,4-b]pyridine (Compound 123)
[0425] Using
(Z)-2-[8-(2-propylbenzimidazol-1-yl)methyl-5,11-dihydrobenzooxepino[3,4-b-
]pyridin-5-ylidene]propiononitrile (0.016 g, 0.038 mmol) obtained
in Example 122, step 1 and in the same manner as in Example 4, the
title compound (compound 123) (0.0073 g, 41%) was obtained.
[0426] ESI-MS m/z: 464 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.88 (t, J=7.4 Hz, 3H), 1.75 (m, 2H), 2.18 (s, 3H), 2.20
(m, 2H), 4.36 (d, J=13.7 Hz, 1H), 4.94 (d, J=16.8 Hz, 1H), 5.08 (d,
J=16.8 Hz, 1H), 5.12 (d, J=13.7 Hz, 1H), 6.18 (s, 1H), 6.68 (d,
J=7.3 Hz, 1H), 6.77 (d, J=7.9 Hz, 1H), 6.99-7.55 (m, 5H), 7.77 (d,
J=6.9 Hz, 1H), 8.51 (d, J=4.6 Hz, 1H).
Example 124
(E)-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-8-(2-propylbe-
nzimidazol-1-yl)methyl-5,11-dihydrobenzooxepino[3,4-b]pyridine
(Compound 124)
[0427] [step 1] Using
(E)-2-(8-chloromethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)pr-
opiononitrile (0.184 g, 0.622 mmol) obtained in Reference Example
B15 and in the same manner as in Example 1,
(E)-2-[8-(2-propylbenzimidazol-1-yl)methyl-5,11-dihydrobenzooxepino[3,4-b-
]pyridin-5-ylidene]propiononitrile (0.220 g, 84%) was obtained.
[step 2] Using
(E)-2-[8-(2-propylbenzimidazol-1-yl)methyl-5,11-dihydrobenzooxepino-
[3,4-b]pyridin-5-ylidene]propiononitrile (0.108 g, 0.26 mmol)
obtained in Example 124, step 1 and in the same manner as in
Example 5, the title compound (compound 124) (0.043 g, 34%) was
obtained.
[0428] ESI-MS m/z: 480 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.97 (t, J=7.6 Hz, 3H), 1.81 (m, 2H), 2.21 (s, 3H), 2.87
(t, J=7.6 Hz, 2H), 4.65 (d, J=14.4 Hz, 1H), 4.95 (d, J=14.4 Hz,
1H), 5.32 (s, 2H), 6.70 (s, 1H), 6.79 (d, J=7.9 Hz, 1H), 7.10-7.32
(m, 5H), 7.49-7.65 (m, 2H), 8.43 (d, J=1.3 Hz, 1H).
Example 125
(E)-8-(2-Propylbenzimidazol-1-yl)methyl-5-(1H-tetrazol-5-yl)methylene-5,11-
-dihydrobenzooxepino[3,4-b]pyridine (compound 125)
[0429] Using
(E)-2-[8-(2-propylbenzimidazol-1-yl)methyl-5,11-dihydrobenzooxepino[3,4-b-
]pyridin-5-ylidene]propiononitrile (0.108 g, 0.26 mmol) obtained in
Example 124, step 1 and in the same manner as in Example 4, the
title compound (compound 125) (0.055 g, 45%) was obtained.
[0430] ESI-MS m/z: 464 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.93 (t, J=7.4 Hz, 3H), 1.75 (m, 2H), 2.24 (s, 3H), 2.79
(t, J=7.4 Hz, 2H), 4.91 (d, J=12.9 Hz, 1H), 5.45 (s, 2H), 5.69 (d,
J=12.9 Hz, 1H), 6.63 (s, 1H), 6.68 (d, J=7.3 Hz, 1H), 7.11-7.21 (m,
4H), 7.37 (d, J=7.9 Hz, 1H), 7.44 (m, 1H), 7.69 (m, 1H), 8.41 (m,
1H).
Reference Example A1
4-Chloro-2-cyclopropylbenzimidazole
[0431] 2-Chloro-6-nitroaniline (3.00 g, 17.4 mmol) and pyridine
(7.0 mL, 86.9 mmol) were dissolved in DMA (17 mL),
cyclopropanecarbonyl chloride (4.0 mL, 43.5) was added and the
mixture was stirred at 50.degree. C. for 3 hr. To the mixture were
added methanol (10 mL) and aqueous ammonia (9 mL), and the mixture
was stirred at room temperature for 30 min. Water (10 mL) was
added, and the precipitated solid was collected by filtration. The
solid was suspended in ethanol (38 mL) and water (38 mL), ferrous
sulfate 7 hydrate (13.86 g, 49.9 mmol) and aqueous ammonia (19 mL)
were added, and the mixture was stirred at 50.degree. C. for 4 hr.
The mixture was filtered, and the filtrate was extracted with ethyl
acetate, washed with brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. Acetic acid (8 mL) was
added to the residue, and the mixture was stirred at 90.degree. C.
for 1 hr. The mixture was concentrated under reduced pressure,
neutralized with aqueous sodium hydroxide solution, and extracted
with ethyl acetate. The organic layer was washed with brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. Ethyl acetate (5 mL) and diisopropyl ether (5 mL) were
added to the residue, and the precipitated solid was collected by
filtration to give the title compound (1.20 g, 36%).
[0432] ESI-MS m/z: 193 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.11-1.25 (m, 4H), 2.01-2.14 (m, 1H), 7.05-7.55 (m,
3H).
Reference Example A2
6-(2-Furanyl)-4-methyl-2-propylbenzimidazole
[0433] Under a nitrogen atmosphere,
6-bromo-4-methyl-2-propylbenzimidazole (WO2004082621; 200 mg, 0.83
mmol) was dissolved in toluene (4 mL), tributyl(2-furanyl)tin (0.78
mL, 2.49 mmol) and tetrakis(triphenylphosphine)palladium (288 mg,
0.25 mmol) were added, and the mixture was stirred at 100.degree.
C. for 3 days. Water was added to the mixture, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate=8/2 to 1/9) to give the
title compound (60 mg, 30%).
[0434] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.03 (t, J=7.3 Hz, 3H),
1.79-1.97 (m, 2H), 2.64 (s, 3H), 2.89 (t, J=7.3 Hz, 2H), 6.45-6.48
(m, 1H), 6.51-6.54 (m, 1H), 6.59 (d, J=4.0 Hz, 1H), 7.37 (s, 1H),
7.75 (s, 1H).
Reference Example A3
4-Methyl-6-(2-oxazolyl)-2-propylbenzimidazole
[0435] [step 1] 6-Methoxycarbonyl-4-methyl-2-propylbenzimidazole
(EP502314; 500 mg, 2.29 mmol) was suspended in ethanol (15 mL), 4
mol/L aqueous sodium hydroxide solution (3.1 ml) was added, and the
mixture was stirred under reflux for 7 hr. The mixture was
concentrated under reduced pressure, and water (20 mL) was added.
Under ice-cooling, the mixture was adjusted to pH 1 with 2 mol/L
hydrochloric acid, and extracted with chloroform. The organic layer
was washed with brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was dissolved in
dichloromethane, aminoacetaldehyde dimethylacetal (0.50 mL, 4.58
mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (527 mg, 2.75
mmol) and 1-hydroxybenzotriazole (421 mg, 2.75 mmol) were added,
and the mixture was stirred at room temperature for 6 hr. To the
mixture were added saturated aqueous sodium hydrogen carbonate
solution (100 mL) and chloroform (100 mL), and the organic layer
was washed with brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to give
6-(2,2-dimethoxyethylcarbamoyl)-4-methyl-2-propylbenzimidazole.
[0436] ESI-MS m/z; 306 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.02 (t, J=7.3 Hz, 3H), 1.82-1.97 (m, 2H), 2.65 (s, 3H),
2.92 (t, J=7.3 Hz, 2H), 3.45 (s, 6H), 3.64 (t, J=5.3 Hz, 2H), 4.52
(t, J=5.3 Hz, 1H), 6.42 (s, 1H), 7.89 (s, 1H).
[step 2] To 7.7% phosphorus pentaoxide-methanesulfonic acid
(Eaton's reagent; 10 mL) was added
6-(2,2-dimethoxyethylcarbamoyl)-4-methyl-2-propylbenzimidazole (400
mg, 1.31 mmol) obtained in step 1, and the mixture was stirred at
130.degree. C. for 7 hr. The reaction solution was added to
ice-cooled aqueous solution (100 mL), and the mixture was stirred
for 30 min. After stirring, saturated aqueous sodium hydrogen
carbonate solution (80 mL) and ethyl acetate (200 mL) were added to
the mixture. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=20/80 to 0/100) to give the
title compound (207 mg, 66%).
[0437] ESI-MS m/z; 242 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.07 (t, J=7.3, 1.8 Hz, 3H), 1.80-1.95 (m, 2H), 2.68 (s,
3H), 2.92 (t, J=7.3 Hz, 2H), 7.25 (d, J=9.9 Hz, 1H), 7.71 (s, 1H),
7.77 (s, 1H), 7.87 (d, J=9.9 Hz, 1H).
Reference Example A4
2,4-Dimethyl-6-phenylbenzimidazole
[0438] [step 1] To a mixture of 4-bromo-2-methylaniline (9.00 g,
48.3 mmol) and acetic anhydride (54 mL) was added dropwise under
ice-cooling fuming nitric acid (8.10 mL, 194 mmol) over 20 min.
Under ice-cooling, the mixture was stirred for 1 hr and water and
ethyl acetate were added to the mixture, and the mixture was
extracted. The organic layer was washed with saturated aqueous
sodium hydrogen carbonate solution and brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. Ethyl
acetate-hexane (1/1, 24 mL) was added to the residue, and the
precipitated solid was collected by filtration. The obtained solid
was suspended in ethanol (40 mL), concentrated hydrochloric acid
(25 mL) was added, and the mixture was stirred under reflux for 4
hr. To the mixture were added ethanol (10 mL) and water (7 mL), and
the mixture was stirred at 90.degree. C. for 30 min. The reaction
solution was allowed to cool to room temperature, and the
precipitated solid was collected by filtration to give
4-bromo-6-methyl-2-nitroaniline (3.87 g, 35%).
[0439] ESI-MS m/z; 232 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.24 (s, 3H), 6.17 (s, 2H), 7.38 (s, 1H), 8.19 (s,
1H).
[step 2] Under a nitrogen atmosphere,
4-bromo-6-methyl-2-nitroaniline (2.80 g, 12.1 mmol) obtained in
step 1 was dissolved in DMF (60 mL), phenylboronic acid (4.40 g,
36.3 mmol), cesium carbonate (7.90 g, 24.2 mmol) and
tetrakis(triphenylphosphine)palladium (1.40 g, 2.42 mmol) were
added, and the mixture was stirred at 100.degree. C. for 4 hr.
Water was added to the mixture, and the mixture was extracted with
ethyl acetate. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=1/1 to 0/1) to give
4-amino-3-methyl-5-nitrobiphenyl (2.25 g, 81%).
[0440] .sup.1H-NMR (CDCl.sub.3, .delta.) 2.32 (s, 3H), 6.21 (s,
2H), 7.29-7.37 (m, 1H), 7.39-7.49 (m, 2H), 7.51-7.63 (m, 3H),
8.27-8.33 (m, 1H).
[step 3] 4-Amino-3-methyl-5-nitrobiphenyl (100 mg, 0.44 mmol)
obtained in step 2 was dissolved in ethanol-ethyl acetate (1/1, 4
mL), and the mixture was stirred in the presence of 10% palladium
carbon (10 mg) under a hydrogen atmosphere at room temperature for
20 hr. The mixture was filtered, and the filtrate was concentrated
under reduced pressure to give 3,4-diamino-5-methylbiphenyl (87 mg,
100%).
[0441] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.26 (s, 3H), 3.34-3.53
(m, 4H), 6.86-6.93 (m, 2H), 7.21-7.28 (m, 1H), 7.35-7.40 (m, 2H),
7.50-7.53 (m, 2H).
[step 4] 3,4-Diamino-5-methylbiphenyl (150 mg, 0.64 mmol) obtained
in step 3 was suspended in acetic acid (4 mL), trimethyl ortho
acetate (0.14 mL, 0.76 mmol) was added, and the mixture was stirred
at 110.degree. C. for 18 hr. Under ice-cooling, 28% aqueous ammonia
solution (5 mL) was added to the mixture, and the mixture was
extracted with ethyl acetate (20 mL). The organic layer was washed
with brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to give the title compound (137
mg, 96%).
[0442] ESI-MS m/z; 223 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.65 (s, 3H), 2.66 (s, 3H), 7.29 (s, 1H), 7.34 (d, J=7.3
Hz, 1H), 7.44 (t, J=7.6 Hz, 2H), 7.53 (s, 1H), 7.62 (d, J=7.6 Hz,
2H).
Reference Example A5
2-(2-Hydroxyethyl)-4-methyl-6-phenylbenzimidazole
[0443] 3,4-Diamino-5-methylbiphenyl (516 mg, 2.20 mmol) obtained in
Reference Example A4, step 3 and 2-hydroxypropionitrile (470 mg,
6.61 mmol) were suspended in water (2 mL), concentrated
hydrochloric acid (1 mL) was added, and the mixture was stirred
under reflux for 2 days. Under ice-cooling, 28% aqueous ammonia
solution was added to the mixture, and the mixture was extracted
with ethyl acetate. The organic layer was washed with brine, dried
over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (chloroform/methanol=97/3 to 90/10) to give the
title compound (260 mg, 47%).
[0444] ESI-MS m/z; 253 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.64 (s, 3H), 3.18 (t, J=5.5 Hz, 2H), 4.13 (t, J=5.5 Hz,
2H), 7.28-7.37 (m, 2H), 7.39-7.48 (m, 2H), 7.51-7.66 (m, 3H).
Reference Example A6
2-(2-Hydroxymethyl)-4-methyl-6-phenylbenzimidazole
[0445] Using 3,4-diamino-5-methylbiphenyl (260 mg, 1.11 mmol)
obtained in Reference Example A4, step 3, and 50%
hydroxyacetonitrile (0.38 ml, 3.33 mmol,) instead of
2-hydroxypropionitrile, and in the same manner as in Reference
Example A5, the title compound (214 mg, 70%) was obtained.
[0446] ESI-MS m/z; 239 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.65 (s, 3H), 4.90 (s, 2H), 7.25 (s, 1H), 7.32 (d, J=7.6
Hz, 1H), 7.43 (t, J=7.6 Hz, 2H), 7.58 (s, 1H), 7.63 (d, J=7.6 Hz,
2H).
Reference Example A7
2-(2-Methoxycarbonylethyl)-4-methyl-6-phenylbenzimidazole
[0447] 4-Amino-3-methyl-5-nitrobiphenyl (400 mg, 1.75 mmol)
obtained in Reference Example A4, step 2 was dissolved in
dichloromethane (5 mL), methyl 4-chloro-4-oxobutyrate (527 mg, 3.50
mmol) was added, and the mixture was stirred for 6 hr. To the
mixture was added saturated aqueous sodium hydrogen carbonate
solution (5 mL), and the mixture was extracted with ethyl acetate
(20 mL). The organic layer was washed with saturated aqueous sodium
hydrogen carbonate solution and brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. Ethyl
acetate-hexane (1/5, 20 mL) was added to the residue, and the
precipitated solid was collected by filtration. The obtained solid
was dissolved in methanol-ethyl acetate (1/1, 20 mL), and the
mixture was stirred in the presence of 10% palladium carbon (90 mg)
under a hydrogen atmosphere at room temperature for 1 day. The
mixture was filtered, and the filtrate was concentrated under
reduced pressure. The residue was dissolved in acetic acid (20 mL),
and the mixture was stirred at 100.degree. C. for 1 hr. The mixture
was concentrated under reduced pressure, saturated aqueous sodium
hydrogen carbonate solution (20 mL) was added, and the mixture was
extracted twice with ethyl acetate (50 mL). The organic layer was
washed with saturated aqueous sodium hydrogen carbonate solution
and brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate=1/1 too/1) to give the
title compound (404 mg, 78%).
[0448] ESI-MS m/z; 295 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.64 (s, 3H), 2.89 (t, J=6.3 Hz, 2H), 3.25 (t, J=6.3 Hz,
2H), 3.75 (s, 3H), 7.27-7.36 (m, 3H), 7.39-7.48 (m, 2H), 7.58-7.65
(m, 2H).
Reference Example B1
(E)-2-(2-Bromomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)ac-
etonitrile
[0449]
(E)-(2-Hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yli-
dene)acetonitrile (JP-B-2526005; 10.00 g, 38.3 mmol) was dissolved
in THF (380 mL), 2,6-lutidine (26.7 mL, 230 mmol), lithium bromide
(19.94 g, 230 mmol) and methanesulfonic anhydride (16.67 g, 95.7
mmol) were added, and the mixture was stirred at room temperature
for 16 hr. Ethyl acetate was added to the mixture, and the organic
layer was washed with brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure to give a residue.
Ethyl acetate (10 mL) and hexane (5 mL) were added to the residue,
and the mixture was filtered to give the title compound (9.18 g,
74%).
[0450] .sup.1H-NMR (CDCl.sub.3, .delta.): 3.11-3.16 (m, 4H), 4.43
(s, 2H), 5.72 (s, 1H), 7.18 (s, 1H), 7.23-7.37 (m, 5H), 7.45 (dd,
J=7.3, 1.7 Hz, 1H).
Reference Example B2
(E)-2-(2-Chloromethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)a-
cetonitrile
[0451]
(E)-(2-Hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yli-
dene)acetonitrile (JP-B-2526005; 2.61 g, 10.0 mmol) was dissolved
in THF (26 mL), triethylamine (2.09 mL, 15.0 mmol), methanesulfonyl
chloride (1.16 mL, 15.0 mmol) and lithium chloride (0.636 g, 15.0
mmol) were added, and the mixture was stirred at 50.degree. C. for
2 hr. Ethyl acetate was added to the mixture, and the organic layer
was washed with brine. The organic layer was dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure.
Isopropyl ether (30 mL) was added to the obtained residue, and the
mixture was filtered to give the title compound (2.59 g, 93%).
[0452] .sup.1H-NMR (CDCl.sub.3, .delta.): 3.11-3.17 (m, 4H), 4.53
(s, 2H), 5.71 (s, 1H), 7.18-7.37 (m, 6H), 7.43-7.47 (m, 1H).
Reference Example B3
(E)-2-(2-Hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
propiononitrile and
(Z)-2-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene-
)propiononitrile
[0453] [step 1]
5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid
(JP-B-2526005, 19.9 g, 79 mmol) and triethyl orthoformate (17.0 mL,
102 mmol) were dissolved in ethanol (130 mL), concentrated sulfuric
acid (1.68 mL, 32 mmol) was added, and the mixture was stirred
under reflux for 12 hr. The mixture was diluted with ethyl acetate,
and the organic layer was washed with saturated aqueous sodium
hydrogen carbonate solution, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (hexane/ethyl acetate=90/10) to
give ethyl
5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2-carboxylate (20.8
g, 94%).
[0454] ESI-MS m/z: 281 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.42 (t, J=7.2 Hz, 3H), 3.21-3.30 (m, 4H), 4.40 (q, J=7.2
Hz, 2H), 7.24 (d, J=7.5 Hz, 1H), 7.34 (td, J=7.5, 1.3 Hz, 1H), 7.46
(td, J=7.5, 1.5 Hz, 1H), 7.92-8.04 (m, 4H).
[step 2] To a solution of sodium hydride (60%, 0.856 g, 21.4 mmol)
and diethyl 1-cyanoethylphosphonate (4.09 g, 21.4 mmol) in DMF (35
mL) was added a solution of ethyl
10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylate (3.0
g, 10.7 mmol) obtained in step 1 in DMF (10 mL) under ice-cooling,
and the mixture was stirred at 80.degree. C. for 3 hr. Water was
added to the mixture, and the mixture was extracted with ethyl
acetate. The organic layer was dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure to give a residue.
The obtained residue was dissolved in THF (50 mL), lithium
borohydride (1.11 g, 50.9 mmol) was added, and the mixture was
stirred at 50.degree. C. for 5 hr. The mixture was neutralized with
2 mol/L hydrochloric acid, and extracted with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (chloroform/ethyl acetate=98/2) to
give
(E)-2-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene-
)propiononitrile (0.730 g, 27%) and
(Z)-2-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene-
)propiononitrile (0.728 g, 27%).
[0455] E-form; .sup.1H-NMR (CDCl.sub.3, .delta.): 2.04 (s, 3H),
2.82-2.95 (m, 2H), 3.27-3.40 (m, 2H), 4.67 (d, (7=5.8 Hz, 2H), 7.08
(d, (7=7.8 Hz, 1H), 7.13-7.29 (m, 5H), 7.41 (dd, (7=7.1, 1.8 Hz,
1H).
[0456] Z-form; .sup.1H-NMR (CDCl.sub.3, .delta.): 2.03 (s, 3H),
2.81-2.97 (m, 2H), 3.26-3.40 (m, 2H), 4.64 (d, J=5.6 Hz, 2H), 7.07
(d, J=7.1 Hz, 1H), 7.16-7.28 (m, 5H), 7.43 (d, J=7.8 Hz, 1H).
Reference Example B4
(E)-2-(8-Hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propionon-
itrile and
(Z)-2-(8-hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-yliden-
e)propiononitrile
[0457] Using methyl
11-oxo-6,11-dihydrodibenzo[b,e]oxepin-8-carboxylate (JP-B-2526005,
1.00 g, 3.73 mmol) and in the same manner as in Reference Example
B3, step 2, the title E-form (0.260 g, 25%) and Z isomer thereof
(0.178 g, 17%) were obtained.
[0458] E-form; .sup.1H-NMR (CDCl.sub.3, .delta.): 2.23 (s, 3H),
4.61 (s, 2H), 4.82 (d, J=12.6 Hz, 1H), 5.45 (d, J=12.6 Hz, 1H),
6.83-6.92 (m, 2H), 7.05 (dd, J=7.8, 1.7 Hz, 1H), 7.18-7.24 (m, 1H),
7.30-7.34 (m, 2H), 7.42 (d, J=8.3 Hz, 1H).
[0459] Z-form; .sup.1H-NMR (CDCl.sub.3, .delta.): 2.03 (s, 3H),
4.72 (br s, 2H), 4.85 (d, J=12.6 Hz, 1H), 5.48 (d, J=12.6 Hz, 1H),
6.82 (dd, J=8.2, 1.1 Hz, 1H), 6.93-6.98 (m, 1H), 7.16 (d, J=7.9 Hz,
1H), 7.22-7.27 (m, 1H), 7.37 (dd, J=7.8, 1.7 Hz, 1H), 7.42 (br s,
1H), 7.51 (dd, J=7.9, 1.6 Hz, 1H).
Reference Example B5
(E)-2-(8-Chloromethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propiononi-
trile
[0460]
(E)-2-(8-Hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)pr-
opiononitrile (2.77 g, 10.0 mmol) obtained in Reference Example B4
was dissolved in THF (28 mL), triethylamine (2.09 mL, 15.0 mmol),
methanesulfonyl chloride (1.16 mL, 15.0 mmol) and lithium chloride
(0.636 g, 15.0 mmol) were added, and the mixture was stirred at
50.degree. C. for 2 hr. Ethyl acetate was added to the mixture, and
the organic layer was washed with brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure.
Isopropyl ether (10 mL) was added to the obtained residue, and the
mixture was filtered to give the title compound (2.87 g, 97%).
[0461] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.27 (s, 3H), 4.59 (s,
2H), 4.87 (d, J=12.8 Hz, 1H), 5.48 (d, J=12.8 Hz, 1H), 6.86-6.95
(m, 2H), 7.07 (dd, J=7.8, 1.8 Hz, 1H), 7.21-7.28 (m, 1H), 7.41-7.50
(m, 3H).
Reference Example B6
(Z)-2-(3-Hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propionon-
itrile
[0462] [step 1] Lithium diisopropylamide (2.0 mol/L
heptane/THF/ethylbenzene solution, 100 mL, 200 mmol) was diluted
with THF (40 mL), a solution of propiononitrile (7.13 mL, 100 mmol)
in THF (40 mL) was added dropwise while stirring at 0.degree. C.
over 15 min. After stirring at 0.degree. C. for 30 min, a solution
of diethyl chlorophosphate (14.4 mL, 100 mmol) in THF (40 mL) was
added dropwise over 45 min. After stirring at room temperature for
2 hr, methyl 11-oxo-6,11-dihydrodibenzo[b,e]oxepine-3-carboxylate
(JP-B-2526005, 10.7 g, 40 mmol) was added, and the mixture was
stirred at room temperature for 1.5 hr. To the mixture were added
ethyl acetate and water, and the mixture was extracted with 3 times
with ethyl acetate. The organic layer was washed with brine, dried
over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate:hexane=15:85) to give
(Z)-11-(1-cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepine-3-carboxylic
acid methyl ester (4.47 g, 14.6 mmol, 37%) and
(E)-11-(1-cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepine-3-carboxylic
acid methyl ester (6.40 g, 21.0 mmol, 53%).
[0463] Z-form; .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.98 (s, 3H),
3.83 (s, 3H), 5.03 (d, J=12.7 Hz, 1H), 5.55 (d, J=12.7 Hz, 1H),
7.33-7.65 (m, 7H).
[0464] E-form; .sup.1H-NMR (DNSO-d.sub.6, .delta.): 2.20 (s, 3H),
3.83 (s, 3H), 5.04 (d, J=12.7 Hz, 1H), 5.57 (d, J=12.7 Hz, 1H),
7.34-7.62 (m, 7H).
[step 2]
(Z)-11-(1-Cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepine-3-car-
boxylic acid methyl ester (0.557 g, 1.82 mmol) was suspended in THF
(9 mL), lithium borohydride (0.199 g, 9.12 mmol) was added and the
mixture was stirred at 50.degree. C. for 8 hr. To the mixture was
added ice, and the mixture was neutralized to pH 2 with 1 mol/L
hydrochloric acid, and extracted twice with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. Isopropyl alcohol
(13 mL) was added to the residue, and the mixture was filtered to
give the title compound (0.364 g, 72%).
[0465] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.03 (s, 3H), 4.60 (s,
2H), 4.85 (d, J=12.6 Hz, 1H), 5.48 (d, J=12.6 Hz, 1H), 6.84 (s,
1H), 6.95 (dd, J=8.1, 1.2 Hz, 1H), 7.15-7.19 (m, 1H), 7.36-7.42 (m,
3H), 7.51 (d, J=8.1 Hz, 1H).
Reference Example B7
(E)-(2-Hydroxymethyl-4H-9,10-dihydrobenzo[4,5]cyclohepta[1,2-b]thiophen-4--
ylidene)acetonitrile and
(Z)-(2-hydroxymethyl-4H-9,10-dihydrobenzo[4,5]cyclohepta[1,2-b]thiophen-4-
-ylidene)acetonitrile
[0466] To a solution of sodium hydride (60%, 0.453 g, 11.3 mmol)
and diethyl cyanomethylphosphonate (2.01 g, 11.3 mmol) in DMF (10
mL) was added a solution of
2-bromo-4H-9,10-dihydrobenzo[4,5]cyclohepta[1,2-b]thiophen-4-one
(Helvetica Chimica Acta, 1966, vol. 26, p 214; 1.66 g, 5.66 mmol)
in DMF (20 mL) under ice-cooling, and the mixture was stirred at
80.degree. C. for 1 hr. Water was added to the mixture, and the
mixture was extracted with ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure to give a residue. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate=85/15) to
give nitrile (1.41 g, 79%). The obtained nitrile (1.41 g, 4.46
mmol), palladium acetate (0.200 g, 0.892 mmol),
1,3-bis(diphenylphosphino)propane (0.368 g, 0.892 mmol) and cesium
carbonate (2.91 g, 8.92 mmol) were dissolved in propanol (28 mL)
and DMF (28 mL) and, under a carbon monoxide atmosphere, the
mixture was stirred at 50.degree. C. for 1 hr. Water was added to
the mixture, and the mixture was extracted with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to give a residue. The residue
was purified by silica gel column chromatography (hexane/ethyl
acetate=80/20) to give propyl ester (0.907 g, 63%). The obtained
propyl ester (0.785 g, 2.43 mmol) was dissolved in THF (24 mL),
lithium borohydride (0.264 g, 12.2 mmol) was added and the mixture
was stirred at 50.degree. C. for 10 hr. The mixture was neutralized
with 2 mol/L hydrochloric acid, and extracted with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate=100/0 to
60/40) to give
(E)-(2-hydroxymethyl-4H-9,10-dihydrobenzo[4,5]cyclohepta[1,2-b]thiop-
hen-4-ylidene)acetonitrile (0.384 mg, 51%) and
(Z)-(2-hydroxymethyl-4H-9,10-dihydrobenzo[4,5]cyclohepta[1,2-b]thiophen-4-
-ylidene)acetonitrile (0.328 mg, 44%).
[0467] E-form; .sup.1H-NMR (CDCl.sub.3, .delta.): 3.07-3.12 (m,
4H), 4.74 (d, J=5.8 Hz, 2H), 5.75 (s, 1H), 6.90 (s, 1H), 7.26-7.39
(m, 3H), 7.49-7.52 (m, 1H).
[0468] Z-form; .sup.1H-NMR (CDCl.sub.3, .delta.): 3.07-3.20 (m,
4H), 4.77 (d, J=6.3 Hz, 2H), 5.45 (s, 1H), 7.18-7.36 (m, 4H), 7.40
(s, 1H).
Reference Example B8
(E)-[2-(6-Carboxy-4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro--
5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile
[0469] [step 1] 6-Methoxycarbonyl-4-methyl-2-propylbenzimidazole
(EP502314; 1.19 g, 5.13 mmol) was dissolved in DMF (15 mL),
potassium tert-butoxide (0.60 g, 5.3 mmol) was added at 0.degree.
C., and the mixture was stirred for 10 min. To this mixture was
added a solution of
(E)-(2-bromomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)ace-
tonitrile obtained in Reference Example B1 in DMF (8 mL), and the
mixture was stirred at room temperature for 2 hr. Ethyl acetate was
added to the mixture, and the organic layer was washed with brine,
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=3/1 tot/3) to give
(E)-[2-(6-methoxycarbonyl-4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-
-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (1.78 g,
73%).
[0470] ESI-MS m/z; 476 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.00 (t, J=7.3 Hz, 3H), 1.75-1.89 (m, 2H), 2.70 (s, 3H),
2.82 (t, J=7.8 Hz, 2H), 3.06 (br s, 4H), 3.88 (s, 3H), 5.33 (s,
2H), 5.67 (s, 1H), 6.68 (s, 1H), 6.81 (dd, J=8.1, 1.4 Hz, 1H),
7.20-7.34 (m, 4H), 7.43 (dd, J=7.4, 1.8 Hz, 1H), 7.74 (d, J=1.0 Hz,
1H), 7.77 (d, J=1.0 Hz, 1H).
[step 2]
(E)-[2-(6-Methoxycarbonyl-4-methyl-2-propylbenzimidazol-1-yl)met-
hyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile
(500 mg, 1.05 mmol) obtained in step 1 was dissolved in ethanol
(7.5 mL), 2 mol/L aqueous sodium hydroxide solution (2.5 mL) was
added, and the mixture was stirred under reflux for 30 min. The
mixture was adjusted to pH 2 with 2 mol/L hydrochloric acid, and
the precipitated solid was collected by filtration to give the
title compound (554 mg) quantitatively.
[0471] ESI-MS m/z; 462 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.01 (t, J=7.4 Hz, 3H), 1.76-1.87 (m, 2H), 2.72 (s, 3H),
2.87 (t, J=7.6 Hz, 2H), 3.08 (br, 4H), 5.35 (s, 2H), 5.67 (s, 1H),
6.78 (s, 1H), 6.83 (d, J=7.9 Hz, 1H), 7.18-7.37 (m, 4H), 7.43 (d,
J=7.9 Hz, 1H), 7.81 (d, J=9.6 Hz, 2H).
Reference Example A16
4-Iodo-2-propylimidazole
[0472] [step 1] 2-Propylimidazole (3.0 g, 27.3 mmol) was dissolved
in dioxane/water (55 mL/55 mL), sodium hydrogen carbonate (8.67 g,
81.8 mmol) and iodine (15.0 g, 59.9 mmol) were added, and the
mixture was stirred at room temperature overnight. Water was added
to the reaction mixture and the mixture was extracted 3 times with
ethyl acetate. The combined organic layer was dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure to give
4,5-diiodo-2-propylimidazole (7.09 g, 72%). [step 2]
4,5-Diiodo-2-propylimidazole (3.0 g, 8.31 mmol) obtained in
Reference Example A16, step 1 was dissolved in ethanol/water (60
mL/60 mL), sodium sulfite (8.40 g, 66.5 mmol) was added, and the
mixture was heated under reflux overnight. After completion of the
reaction, the mixture was extracted 3 times with chloroform. The
combined organic layer was dried over anhydrous magnesium sulfate,
and concentrated under reduced pressure to give
4-iodo-2-propylimidazole (1.73 g, 88%).
[0473] ESI-MS m/Z; 237 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.95 (t, J=7.5 Hz, 3H), 1.60-1.83 (m, 2H), 2.74 (t, J=7.6
Hz, 2H), 7.06 (s, 1H).
Reference Example A8
4-Phenyl-2-propylimidazole
[0474] [step 1] 4-Iodo-2-propylimidazole obtained in Reference
Example A16 was dissolved in dioxane/water (2 mL/1 mL),
phenylboronic acid (0.108 g, 0.889 mmol),
1,1-bisdiphenylphosphinoferrocene dichloropalladium (0.052 g, 0.064
mmol) and sodium carbonate (0.202 g, 1.91 mmol) were added, and the
mixture was heated under reflux for 3 hr. The reaction mixture was
concentrated under reduced pressure, and the obtained residue was
purified by silica gel column chromatography (hexane/ethyl
acetate=1/2) to give 4-phenyl-2-propylimidazole (0.091 g, 77%).
[0475] ESI-MS m/z; 187 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.86 (t, J=7.5 Hz, 3H), 1.52-1.86 (m, 2H), 2.65 (t, J=7.5
Hz, 2H), 7.12-7.38 (m, 4H), 7.60-7.78 (m, 2H), 11.58 (br s,
1H).
Reference Example A9
2-Propyl-4-(4-pyridyl)imidazole
[0476] [step 1] 4-Iodo-2-propylimidazole obtained in Reference
Example A16 was dissolved in dioxane/water (2 mL/1 mL),
4-pyridineboronic acid (0.108 g, 0.889 mmol),
1,1-bisdiphenylphosphinoferrocene dichloropalladium (0.052 g, 0.064
mmol) and sodium carbonate (0.202 g, 1.91 mmol) were added, and the
mixture was heated under reflux for 3 hr. The reaction mixture was
concentrated under reduced pressure, and the obtained residue was
purified by silica gel column chromatography (hexane/ethyl
acetate=1/2) to give 2-propyl-4-(4-pyridyl)imidazole (0.044 g,
37%).
[0477] ESI-MS m/z; 188 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.65-1.13 (m, 3H), 1.54-1.98 (m, 2H), 2.43-2.98 (m, 2H),
6.82-7.11 (m, 1H), 7.18-7.83 (m, 3H), 8.32-8.61 (m, 1H), 9.97 (br
s, 1H).
Reference Example A10
4-Methyl-6-(5-methyl-1,3-oxazol-2-yl)-2-propylbenzimidazole
[0478] [step 1] 6-Methoxycarbonyl-4-methyl-2-propylbenzimidazole
(EP502314; 2.1 g, 9.04 mmol) was suspended in ethanol (65 mL), 4
mol/L aqueous sodium hydroxide solution (21 mL) was added, and the
mixture was stirred under reflux for 3 hr. The mixture was
concentrated under reduced pressure, and water (80 mL) was added.
Under ice-cooling, the mixture was adjusted to pH 1 with 2 mol/L
hydrochloric acid, and the precipitated solid was collected by
filtration. The obtained solid (300 mg, 1.38 mmol) was dissolved in
DMF (12 mL), 1-amino-2-propanol (0.21 mL, 2.75 mmol),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (316 mg, 1.65 mmol)
and 1-hydroxybenzotriazole (253 mg, 1.65 mmol) were added, and the
mixture was stirred at room temperature for 13 hr. To the mixture
were added saturated aqueous sodium hydrogen carbonate solution (40
mL) and chloroform (150 mL), and the organic layer was washed with
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. Chloroform (5 mL) was added to the residue,
and the mixture was stirred at room temperature for 1 hr, and
filtered to give
6-(2-hydroxypropylcarbamoyl)-4-methyl-2-propylbenzimidazole (255
mg, 68%). [step 2] Under a nitrogen atmosphere,
6-(2-hydroxypropylcarbamoyl)-4-methyl-2-propylbenzimidazole (240
mg, 0.87 mmol) obtained in step 1 was dissolved in dichloromethane
(11 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one
(555 mg, 1.31 mmol) was added at 0.degree. C., and the mixture was
stirred at room temperature for 4 hr. To the mixture was added
saturated aqueous sodium hydrogen carbonate solution (20 mL), and
the mixture was extracted with chloroform. The organic layer was
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (chloroform/methanol=97/3 to 90/10) to give
6-(2-oxopropylcarbamoyl)-4-methyl-2-propylbenzimidazole (208 mg,
87%). [step 3] To
6-(2-oxopropylcarbamoyl)-4-methyl-2-propylbenzimidazole (145 mg,
0.53 mmol) obtained in step 2 was added concentrated sulfuric acid
(1.6 mL), and the mixture was stirred at 130.degree. C. for 1.5 hr.
To the ice-cooled mixture were added 4 mol/L aqueous sodium
hydroxide solution (8 mL) and ethyl acetate (15 mL), and the
mixture was stirred for 1 hr and extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography
(chloroform/methanol=98/2 to 93/7) to give the title compound (93
mg, 69%).
[0479] ESI-MS m/z; 256 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.90 (t, J=7.3 Hz, 3H), 1.73-1.89 (m, 2H), 2.38 (d, J=0.7
Hz, 3H), 2.55 (s, 3H), 2.86 (t, J=7.7 Hz, 2H), 6.80 (d, J=1.5 Hz,
1H), 7.68 (s, 1H), 8.00 (s, 1H).
Reference Example A11
4-Methyl-6-(4-methyl-1,3-oxazol-2-yl)-2-propylbenzimidazole
[0480] [step 1] 6-Methoxycarbonyl-4-methyl-2-propylbenzimidazole
(EP502314; 2.1 g, 9.04 mmol) was suspended in ethanol (65 mL), 4
mol/L aqueous sodium hydroxide solution (21 mL) was added, and the
mixture was stirred under reflux for 3 hr. The mixture was
concentrated under reduced pressure, and water (80 mL) was added.
Under ice-cooling, the mixture was adjusted to pH 1 with 2 mol/L
hydrochloric acid, and the precipitated solid was collected by
filtration. The obtained solid (289 mg, 1.32 mmol) was dissolved in
DMF (11 mL), 2-amino-1-propanol (0.21 mL, 2.65 mmol),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (305 mg, 1.59 mmol)
and 1-hydroxybenzotriazole (243 mg, 1.59 mmol) were added, and the
mixture was stirred at room temperature for 15 hr. To the mixture
were added saturated aqueous sodium hydrogen carbonate solution (40
mL) and water, and the mixture was extracted with ethyl acetate
(150 mL). The organic layer was dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography
(chloroform/methanol=95/5 to 89/11) to give
N-(1-hydroxypropan-2-yl)-4-methyl-2-propyl-1H-benzimidazole-6-carboxamide
(267 mg, 73%). [step 2] Under a nitrogen atmosphere,
N-(1-hydroxypropan-2-yl)-4-methyl-2-propyl-1H-benzimidazole-6-carboxamide
(85 mg, 0.31 mmol) obtained in step 1 was dissolved in
dichloromethane (4 mL),
1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (196 mg,
0.46 mmol) was added at 0.degree. C., and the mixture was stirred
at room temperature for 4 hr. To the mixture was added saturated
aqueous sodium hydrogen carbonate solution (20 mL), and the mixture
was extracted with chloroform. The organic layer was dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(chloroform/methanol=94/6 to 90/10) to give
4-methyl-N-(1-oxopropan-2-yl)-2-propyl-1H-benzimidazole-6-carboxamide
(42 mg, 50%). [step 3] To
4-methyl-N-(1-oxopropan-2-yl)-2-propyl-1H-benzimidazole-6-carboxamide
(40 mg, 0.15 mmol) obtained in step 2 was added phosphorus
pentaoxide-methanesulfonic acid (Eaton's reagent, 1 mL), and the
mixture was stirred at 130.degree. C. for 1.5 hr. To the ice-cooled
mixture was added 4 mol/L aqueous sodium hydroxide solution (5 mL),
and the mixture was stirred for 1 hr, and extracted with ethyl
acetate. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (chloroform/methanol=97/3 to 93/7) to give the title
compound (20 mg, 54%).
[0481] ESI-MS m/z; 256 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.92 (t, J=7.3 Hz, 3H), 1.74-1.89 (m, 2H), 2.22 (d, J=1.1
Hz, 3H), 2.56 (s, 3H), 2.86 (t, J=7.7 Hz, 2H), 7.38-7.41 (m, 1H),
7.71-7.74 (m, 1H), 7.95-8.00 (m, 1H).
Reference Example A12
Methyl 2-propyl-1H-benzimidazole-4-carboxylate
[0482] [step 1] To methyl 2-aminobenzoate (1.5 g, 9.92 mmol) was
added butyric anhydride (4.9 mL, 29.76 mmol), and the mixture was
stirred at room temperature for 2 hr. Under ice-cooling, fuming
nitric acid (1.6 mL) was added dropwise to the mixture, and the
mixture was stirred at 0.degree. C. for 20 min. The mixture was
adjusted to pH 7 with water and 4 mol/L aqueous sodium hydroxide
solution, and extracted with ethyl acetate (150 mL). The organic
layer was dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate=100/0 to 60/40) to give
methyl 2-butyramido-3-nitrobenzoate (1.26 g, 48%). [step 2] Methyl
2-butyramido-3-nitrobenzoate (1.65 g, 6.2 mmol) obtained in step 1
was dissolved in methanol (34 mL), and the mixture was stirred in
the presence of 10% palladium carbon (413 mg) under a hydrogen
atmosphere at room temperature for 6 hr. The mixture was filtered,
and the filtrate was concentrated under reduced pressure to give
methyl 3-amino-2-butyramidobenzoate (1.46 g, 100%). [step 3] To
methyl 3-amino-2-butyramidobenzoate (1.46 g, 6.2 mmol) obtained in
step 2 was added acetic acid (9.0 mL), and the mixture was stirred
at 80.degree. C. for 1.5 hr. The mixture was concentrated under
reduced pressure, saturated aqueous sodium hydrogen carbonate
solution (300 mL) was added, and the mixture was extracted with
ethyl acetate. The organic layer was dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/ethyl
acetate=80/20 to 50/50) to give the title compound (1.18 g,
87%).
[0483] ESI-MS m/z; 219 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.06 (t, (7=7.3 Hz, 3H), 1.85-2.02 (m, 2H), 2.94 (t,
J=7.7 Hz, 2H), 4.00 (s, 3H), 7.27 (t, J=7.7 Hz, 1H), 7.85 (dd,
J=7.7, 0.7 Hz, 1H), 7.92 (dd, J=8.1, 0.7 Hz, 1H), 10.15 (br s,
1H).
Reference Example A13
2-Methoxymethylbenzimidazole
[0484] 2-Chloromethylbenzimidazole (1.67 g, 10 mmol) was suspended
in methanol (34 mL), 28% sodium methoxide methanol solution (9.6
mL, 50 mmol) and water (50 mL) were added, and the mixture was
stirred at room temperature for 20 min. The precipitated solid was
collected by filtration, and purified by silica gel column
chromatography (chloroform/methanol=100/0 to 93/7) to give the
title compound (303 mg, 19%).
[0485] ESI-MS m/z; 163 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 3.49 (s, 3H), 4.79 (s, 2H), 7.27-7.31 (m, 2H), 7.59-7.64
(m, 2H).
Reference Example A14
4-Chloro-2-methoxymethylbenzimidazole
[0486] [step 1] 3-Chloro-2-nitroaniline (2.0 g, 11.6 mmol) was
dissolved in dichloromethane (58 mL), triethylamine (2.6 mL, 18.5
mmol) and methoxyacetyl chloride (1.4 mL, 15.1 mmol) were added at
0.degree. C., and the mixture was stirred under reflux for 18 hr.
To the mixture was added 4 mol/L hydrochloric acid (90 mL), and the
mixture was extracted with chloroform. The organic layer was washed
with saturated aqueous sodium hydrogen carbonate solution and
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate=90/10 to 50/50) to give
N-(3-chloro-2-nitrophenyl)-2-methoxyacetamide (1.7 g, 62%). [step
2] N-(3-Chloro-2-nitrophenyl)-2-methoxyacetamide (900 mg, 3.68
mmol) obtained in step 1 was dissolved in ethanol (7.4 mL), tin
chloride dihydrate (4.0 g, 17.7 mmol) was added and the mixture was
stirred at 100.degree. C. for 4 hr. The mixture was adjusted to pH
10 with 4 mol/L aqueous sodium hydroxide solution and filtered. The
filtrate was extracted with ethyl acetate, and the organic layer
was dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure to give the title compound (710 mg, 98%).
[0487] ESI-MS m/z; 197 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 3.53 (s, 3H), 4.81 (s, 2H), 7.16-7.23 (m, 1H), 7.26-7.29
(m, 1H), 7.50 (dd, J=7.9, 0.9 Hz, 1H).
Reference Example A15
(2-Propylbenzimidazol-4-yl)propan-2-ol
[0488] [step 1] To a mixture of methyl 2-amino-5-bromobenzoate (2.3
g, 10.0 mmol) and propionic anhydride (14 mL) was added dropwise
fuming nitric acid (2.1 mL, 50.0 mmol) under ice-cooling. After
stirring at 70.degree. C. for 15 min, water and ethyl acetate were
added to the mixture, and the mixture was extracted. The organic
layer was washed with saturated aqueous sodium hydrogen carbonate
solution and brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate=70/30) to
give methyl 3-amino-5-bromo-2-butylamidobenzoate (1.23 g, 36%).
[step 2] Methyl 3-amino-5-bromo-2-butylamidobenzoate (1.22 g, 3.53
mmol) obtained in step 1 was dissolved in methanol (20 mL) and the
mixture was stirred in the presence of 10% palladium carbon (240
mg) under a hydrogen atmosphere at room temperature for 7 hr. The
mixture was filtered, and the filtrate was concentrated under
reduced pressure. The residue was dissolved in acetic acid (1 mL),
and the mixture was stirred at 100.degree. C. for 1 hr. The mixture
was concentrated under reduced pressure, and the residue was
purified by silica gel column chromatography
(chloroform/methanol=90/10) to give methyl
2-propylbenzimidazole-4-carboxylate (0.299 g, 39%). [step 3] Methyl
2-propylbenzimidazole-4-carboxylate (0.295 g, 1.35 mmol) obtained
in step 2 was dissolved in THF (10 mL), 3 mol/L methylmagnesium
chloride THF solution (4.5 mL, 13 mmol) was added under
ice-cooling, and the mixture was stirred at room temperature for 1
hr. To the mixture were added water and ethyl acetate, and the
mixture was extracted. The organic layer was washed with saturated
aqueous sodium hydrogen carbonate solution and brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (chloroform/methanol=90/10) to give the title
compound (0.201 g, 68%).
[0489] ESI-MS m/z: 219 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.03 (t, J=7.3 Hz, 3H), 1.71 (s, 6H), 1.95-1.82 (m, 2H),
2.87 (t, J=7.5 Hz, 2H), 7.58-6.70 (m, 3H), 9.92-9.88 (m, 1H).
Reference Example B9
(E)-2-(8-Hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)cycloprop-
ylacetonitrile
[0490] [step 1] N-Lithium diisopropylamide (2.0 mol/L
heptane/THF/ethylbenzene solution, 26 mL, 51.9 mmol) was diluted
with THF (40 mL), cyclopropylacetonitrile (2.4 mL, 25.9 mmol) was
added dropwise over 15 min with stirring at 0.degree. C. After
stirring at room temperature for 1 hr, diethyl chlorophosphate (3.7
mL, 25.9 mmol) was added dropwise at 0.degree. C. After stirring at
room temperature for 2 hr, a solution (20 mL) of
8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-one (WO1990015599, 2.50
g, 8.65 mmol) in DMF was added, and the mixture was stirred at room
temperature for 1.5 hr. To the mixture were added ethyl acetate and
water, and the mixture was extracted 3 times with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(hexane/ethyl acetate=9/1) to give
(E)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)cyclopropylaceto-
nitrile and
(Z)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)cyclopropylaceto-
nitrile (1.14 g, 37%). [step 2]
(E)-2-(8-Bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)cyclopropylaceto-
nitrile and
(Z)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)cyclopropylaceto-
nitrile (1.14 g, 3.24 mmol) obtained in step 1 were dissolved in
DMF/n-PrOH (12 mL/6 mL), palladium acetate (0.217 g, 0.972 mmol),
1,3-bisdiphenylphosphinopropane (0.400 g, 0.972 mmol) and cesium
carbonate (1.26 g, 3.89 mmol) were added, and the mixture was
stirred at 70.degree. C. for 3 hr under a carbon monooxide
atmosphere. Ethyl acetate and water were added to the reaction
mixture, and the mixture was extracted 3 times with ethyl acetate.
The combined organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=50/50) to give propyl
(E)-11-cyanocyclopropylmethylene-6,11-dihydrodibenzo[b,e]oxepine-8-carbox-
ylate and propyl
(Z)-11-cyanocyclopropylmethylene-6,11-dihydrodibenzo[b,e]oxepine-8-carbox-
ylate (0.880 g, 75%). [step 3] Propyl
(E)-11-cyanocyclopropylmethylene-6,11-dihydrodibenzo[b,e]oxepine-8-carbox-
ylate and propyl
(Z)-11-cyanocyclopropylmethylene-6,11-dihydrodibenzo[b,e]oxepine-8-carbox-
ylate (0.880 g, 2.45 mmol) obtained in step 2 were dissolved in
THF, lithium borohydride (0.267 g, 12.3 mmol) was added, and the
mixture was stirred with heating at 60.degree. C. for 3 hr. Under
ice-cooling, 2 mol/L hydrochloric acid was added, and the mixture
was neutralized with sodium hydrogen carbonate, and extracted 3
times with ethyl acetate. The combined organic layer was dried over
anhydrous magnesium sulfate, and the solvent was evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (chloroform) to give
(E)-2-(8-hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)cyclopro-
pylacetonitrile (0.210 g, 28%).
[0491] ESI-MS m/z; 304 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.79-1.17 (m, 4H), 1.67 (t, J=6.0 Hz, 1H), 1.96-2.14 (m,
1H), 4.72 (d, J=6.0 Hz, 2H), 4.88 (d, J=12.6 Hz, 1H), 5.55 (d,
J=12.6 Hz, 1H), 6.79-7.02 (m, 2H), 7.19-7.30 (m, 1H), 7.32-7.52 (m,
4H).
Reference Example B10
(E)-2-(2-Hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridine)propiononit-
rile
[0492] [step 1] To a solution (100 mL) of
5,11-dihydrobenzooxepino[3,4-b]pyridine (Synthesis, 1997, 1,
113-116, 5.00 g, 23.7 mmol) in chloroform was added
m-chloroperbenzoic acid (4.89 g, 28.4 mmol), and the mixture was
stirred at room temperature overnight. To the reaction mixture was
added sodium hydrogen carbonate, and the mixture was extracted 3
times with chloroform. The combined organic layer was dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The obtained residue was dissolved in chloroform (10 mL),
phosphorus oxychloride (35 mL) was added and the mixture was
stirred with heating at 90.degree. C. for 3 hr. The reaction
mixture was concentrated under reduced pressure, the obtained black
oil was dissolved in ethyl acetate, and the solution was added
dropwise to aqueous sodium hydrogen carbonate solution under
ice-cooling. The mixture was extracted 3 times with ethyl acetate,
and the combined organic layer was dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(hexane/ethyl acetate=4/1) to give
2-chloro-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-one (3.50 g,
59%). [step 2] N-Lithium diisopropylamide (2.0 mol/L
heptane/THF/ethylbenzene solution, 20 mL, 39.8 mmol) was diluted
with THF (25 mL), propionitrile (1.4 mL, 19.9 mmol) was added
dropwise over 15 min with stirring at 0.degree. C. After stirring
at room temperature for 1 hr, diethyl chlorophosphate (2.9 mL, 19.9
mmol) was added dropwise at 0.degree. C. After stirring at room
temperature for 2 hr, a solution (20 mL) of
2-chloro-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-one (1.95 g, 7.96
mmol) in DMF was added, and the mixture was stirred at room
temperature for 1.5 hr. To the mixture were added ethyl acetate and
water, and the mixture was extracted 3 times with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(hexane/ethyl acetate=9/1) to give
(E)-2-(2-chloro-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiono-
nitrile and
(Z)-2-(2-chloro-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiono-
nitrile (1.79 g, 80%). [step 3] Using
(E)-2-(2-chloro-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiono-
nitrile and
(Z)-2-(2-chloro-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiono-
nitrile (0.890 g, 3.16 mmol) obtained in Reference Example B10,
step 2, instead of
(E)-2-(3-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)cyclopropylaceto-
nitrile and
(Z)-2-(3-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)cyclopropylaceto-
nitrile, and in the same manner as in Reference Example B9, step 2,
propyl
(E)-5-(1-cyanoethylidene)-5,11-dihydrobenzooxepino[3,4-b]pyridine-2-carbo-
xylate (0.374 g, 35%) and propyl
(Z)-5-(1-cyanoethylidene)-5,11-dihydrobenzooxepino[3,4-b]pyridine-2-carbo-
xylate (0.203 g, 20%) were obtained. [step 4] Using propyl
(E)-5-(1-cyanoethylidene)-5,11-dihydrobenzooxepino[3,4-b]pyridine-2-carbo-
xylate (0.370 g, 1.11 mmol) obtained in Reference Example B10, step
3 instead of propyl
(E)-11-cyanocyclopropylmethylene-6,11-dihydrodibenzo[b,e]oxepine-8-carbox-
ylate and propyl
(Z)-11-cyanocyclopropylmethylene-6,11-dihydrodibenzo[b,e]oxepine-8-carbox-
ylate, and in the same manner as in Reference Example B9, step 3,
(E)-2-(2-hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)p-
ropiononitrile (0.191 g, 62%) was obtained.
[0493] ESI-MS m/z; 279 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.10 (s, 3H), 4.73-4.86 (m, 2H), 4.95-5.19 (m, 1H),
5.46-5.66 (m, 1H), 6.90-7.13 (m, 2H), 7.21-7.38 (m, 2H), 7.46-7.60
(m, 2H).
Reference Example B11
(E)-2-(8-Hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)pentaneni-
trile
[0494] [step 1] Using pentanenitrile (2.7 mL, 25.9 mol) instead of
cyclopropylacetonitrile, and in the same manner as in Reference
Example B9, step 1,
(E)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)pentanenitrile
and
(Z)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)pentanenitri-
le (1.90 g, 51%) were obtained. [step 2] Using
(E)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)pentanenitrile
and
(Z)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)pentanenitri-
le (1.9 g, 5.37 mmol) obtained in Reference Example B11, step 1,
instead of
(E)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)cyclopropylac-
etonitrile and
(Z)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)cyclopropylaceto-
nitrile, and in the same manner as in Reference Example B9, step 2,
propyl
(E)-11-(1-cyanobutylidene)-6,11-dihydrodibenzo[b,e]oxepine-8-carboxylate
and propyl
(Z)-11-(1-cyanobutylidene)-6,11-dihydrodibenzo[b,e]oxepine-8-carboxylate
(1.05 g, 54%) were obtained. [step 3] Using propyl
(E)-11-(1-cyanobutylidene)-6,11-dihydrodibenzo[b,e]oxepine-8-carboxylate
and propyl
(Z)-11-(1-cyanobutylidene)-6,11-dihydrodibenzo[b,e]oxepine-8-carboxylate
(1.05 g, 2.91 mmol) instead of propyl
(E)-11-(1-cyanocyclopropylmethylene)-6,11-dihydrodibenzo[b,e]oxepine-8-ca-
rboxylate and propyl
(Z)-11-(1-cyanocyclopropylmethylene)-6,11-dihydrodibenzo[b,e]oxepine-8-ca-
rboxylate, and in the same manner as in Example B9, step 3,
(E)-2-(8-hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)pentanen-
itrile (0.370 g, 41%) was obtained.
[0495] ESI-MS m/z; 306 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.99 (t, J=7.2 Hz, 3H), 1.65-1.86 (m, 2H), 2.49-2.65 (m,
2H), 4.72 (d, J''=6.0 Hz, 2H), 4.88 (d, J=12.6 Hz, 1H), 5.50 (d,
J=12.6 Hz, 1H), 6.83-6.99 (m, 2H), 6.99-7.09 (m, 1H), 7.20-7.30 (m,
1H), 7.33-7.43 (m, 2H), 7.43-7.52 (m, 1H).
Reference Example B12
(E)-11-(2-Fluoro-8-hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-5-ylidene)-
propiononitrile
[0496] [step 1] 5-Bromophthalide (6.00 g, 28.2 mmol) was dissolved
in DMF (10 mL), 4-fluorophenol (3.15 g, 28.2 Jinni) was added, and
the mixture was heated to 120.degree. C. 28% Sodium methoxide
methanol solution (5.5 mL, 28.2 mmol) was added and the mixture was
stirred with heating for 4 hr. 2 mol/L Hydrochloric acid was added
dropwise to the reaction mixture to neutralize the reaction
mixture, and the mixture was extracted 3 times with chloroform. The
combined organic layer was dried over anhydrous magnesium sulfate,
and concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography
(chloroform/methanol=9/1) to give
4-bromo-2-(4-fluorophenoxy)methylbenzoic acid (3.37 g, 36%). [step
2] 4-Bromo-2-(4-fluorophenoxy)methylbenzoic acid (3.37 g, 10.4
mmol) obtained in step 1 was dissolved in dichloromethane (35 mL),
trifluoroacetic anhydride (2.2 mL) and boron trifluoride diethyl
ether complex (0.091 mL, 0.726 mmol) were added, and the mixture
was stirred at room temperature for 6 hr. 2 mol/L Aqueous sodium
hydroxide solution was added to the reaction mixture, and the
mixture was extracted 3 times with dichloromethane. The combined
organic layer was dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The obtained residue was
crystallized from ethanol and collected by filtration to give
8-bromo-2-fluoro-6,11-dihydrodibenzo[b,e]oxepin-11-one (1.10 g,
34%). [step 3] Using
8-bromo-2-fluoro-6,11-dihydrodibenzo[b,e]oxepin-11-one (1.10 g,
3.58 mmol) obtained in step 2 instead of
2-chloro-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-one, and in the
same manner as in Reference Example B10, step 2,
(E)-2-[8-bromo-2-fluoro-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propion-
onitrile and
(Z)-2-[8-bromo-2-fluoro-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propion-
onitrile (0.980 g, 79%) was obtained. [step 4] Using
(E)-2-[8-bromo-2-fluoro-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propion-
onitrile and
(Z)-2-[8-bromo-2-fluoro-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propion-
onitrile (0.980 g, 2.85 mmol) obtained in step 3 instead of
(E)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)cyclopropylaceto-
nitrile and
(Z)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)cyclopropylaceto-
nitrile, and in the same manner as in Reference Example B9, step 2,
propyl
(E)-11-(1-cyanoethylidene)-2-fluoro-6,11-dihydrodibenzo[b,e]oxepine-8-car-
boxylate (0.210 g, 21%) was obtained. [step 5] Using propyl
(E)-11-(1-cyanoethylidene)-2-fluoro-6,11-dihydrodibenzo[b,e]oxepine-8-car-
boxylate (0.210 g, 0.598 mmol) obtained in step 4 instead of propyl
(E)-11-cyanocyclopropylmethylene-6,11-dihydrodibenzo[b,e]oxepine-8-carbox-
ylate and propyl
(Z)-11-cyanocyclopropylmethylene-6,11-dihydrodibenzo[b,e]oxepine-8-carbox-
ylate, and in the same manner as in Reference Example B9, step 3,
(E)-2-(2-fluoro-8-hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene-
)propiononitrile (0.230 g, 100%) was obtained.
[0497] ESI-MS m/z; 296 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.20-2.36 (m, 3H), 4.85 (s, 3H), 5.33-5.54 (m, 1H),
6.74-6.90 (m, 2H), 6.90-7.03 (m, 3H), 7.20-7.54 (m, 3H).
Reference Example B13
(E)-2-(8-Bromomethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)acetonitril-
e
[0498] [step 1] Under ice-cooling, sodium hydride (1.9 g, 47.13
mmol) was suspended in DMF (20 mL), a solution of diethyl
cyanomethylsulfonate (9.2 mL, 56.55 mmol) in DMF (20 mL) was
gradually added dropwise, and the mixture was stirred at room
temperature for 1 hr. To the mixture was added a solution of
8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-one (WO9015599; 11 g,
37.70 mmol) in DMF (80 mL), and the mixture was stirred at room
temperature for 2 hr. To the mixture was added water (80 mL), and
the mixture was stirred at room temperature for 30 min. The
precipitated solid was collected by filtration to give
(E)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)acetonitrile
and
(Z)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)acetonitrile
as a mixture (11.48 g, 97%, E/Z=3/1). [step 2] A mixture (11.48 g,
36.78 mmol) of
(E)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)acetoni-
trile and
(Z)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)acetoni-
trile obtained in step 1, palladium acetate (0.31 g, 1.84 mmol),
1,3-bisdiphenylphosphinopropane (0.76 g, 1.84 mmol) and cesium
carbonate (17.98 g, 55.17 mmol) were suspended in ethanol (57 mL)
and DMF (57 mL), and the mixture was stirred under a carbon
monoxide atmosphere at 70.degree. C. for 1.5 hr. To the mixture was
added 2 mol/L aqueous sodium hydroxide solution (25 mL), and the
mixture was stirred at 70.degree. C. for 3 hr. Under ice-cooling,
the mixture was adjusted to pH=3 with 2 mol/L hydrochloric acid,
and extracted with ethyl acetate. The organic layer was washed with
water and brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue (8.2 g, 29.39
mmol) was dissolved in THF (50 mL), borane-THF 1 mol/L solution (44
mL, 44.09 mmol) was added under ice-cooling, and the mixture was
stirred at room temperature for 4 hr. To the mixture were added
ethyl acetate (100 mL) and water (50 mL), and the mixture was
stirred at 50.degree. C. for 1.5 hr, and extracted with ethyl
acetate. The organic layer was washed with 1 mol/L hydrochloric
acid, saturated aqueous sodium hydrogen carbonate solution and
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate=90/10 to 60/40) to give
(E)-2-(8-hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)acetonit-
rile (2.65 g, 34%) and
(Z)-2-(8-hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)acetonit-
rile (962 mg, 12%). [step 3]
(E)-2-(8-Hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)acetonit-
rile (3.5 g, 13.3 mmol) obtained in step 2 was dissolved in THF
(133 mL), 2,6-lutidine (9.3 mL, 79.8 mmol), lithium bromide (6.9 g,
79.8 mmol) and methanesulfonic anhydride (5.8 g, 33.3 mmol) were
added, and the mixture was stirred at room temperature for 5 hr. To
the mixture was added water (50 mL), and the mixture was extracted
with ethyl acetate (200 mL). The organic layer was washed with 1
mol/L hydrochloric acid (300 mL), saturated aqueous sodium hydrogen
carbonate solution (200 mL) and brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. To the
residue was added silica gel and the mixture was suction filtered,
and the filtrate was concentrated under reduced pressure to give
the title compound (3.63 g, 84%).
[0499] ESI-MS m/z; 326 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 4.77 (s, 2H), 5.19 (s, 2H), 6.40 (s, 1H), 6.84-6.91 (m,
1H), 6.98-7.06 (m, 1H), 7.31-7.42 (m, 1H), 7.44-7.51 (m, 1H),
7.54-7.70 (m, 3H).
Reference Example B14
(Z)-2-(8-Chloromethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)pro-
piononitrile
[0500] [step 1] 4-Azaphthalide (15.0 g, 111.0 mmol) and
3-bromophenol (21.0 g, 121.4 mmol) were suspended in xylene (450
mL), and 28% sodium methoxide methanol solution (31.5 mL, 166.5
mmol) was added dropwise at 140.degree. C. After stirring at
140.degree. C. for 1 hr, DMF (10 ml) was added and the mixture was
further stirred for 3 hr. Water and toluene were added to the
reaction mixture, and the mixture was partitioned. The aqueous
layer was neutralized with hydrochloric acid and the precipitated
solid was collected by filtration to give
2-(3-bromophenoxymethyl)nicotinic acid (16.75 g, 49%). [step 2]
2-(3-Bromophenoxymethyl)nicotinic acid (10.0 g, 32.5 mmol) obtained
in step 1 and polyphosphoric acid (70 g) were stirred at
170.degree. C. for 3 hr. The reaction mixture was added to ice, and
the mixture was neutralized with aqueous sodium hydroxide solution
and extracted with ethyl acetate. The organic layer was washed with
brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (chloroform) to give
8-bromo-5-oxo-5,11-dihydrobenzooxepino[3,4-b]pyridine (2.52 g,
27%). [step 3] Using
8-bromo-5-oxo-5,11-dihydrobenzooxepino[3,4-b]pyridine (3.70 g, 12.8
mmol) obtained in step 2 and in the same manner as in Reference
Example B10, step 2,
(Z)-2-(8-hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)p-
ropiononitrile (0.086 g, 2%) and
(E)-2-(8-hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)p-
ropiononitrile (0.224 g, 6%) were obtained. [step 4] Using
(Z)-2-(8-hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)p-
ropiononitrile (0.084 g, 0.30 mmol) obtained in step 3 and in the
same manner as in Reference Example B2, the title compound (0.056
g, 63%) was obtained.
[0501] ESI-MS m/z: 297 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.07 (s, 3H), 4.50 (s, 2H), 5.10 (brs, 1H), 5.54 (brs,
1H), 7.01 (d, J=1.7 Hz, 1H), 7.07 (dd, J=7.9, 1.7 Hz, 1H), 7.32
(dd, J=7.9, 5.0 Hz, 1H), 7.55-7.50 (m, 2H), 8.59 (dd, J=4.6, 1.7
Hz, 1H).
Reference Example B15
(E)-2-(8-Chloromethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)pro-
piononitrile
[0502] Using
(E)-2-(8-hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)p-
ropiononitrile (0.222 g, 0.80 mmol) obtained in Reference Example
B14, step 3 and in the same manner as in Reference Example B2, the
title compound (0.186 g, 78%) was obtained.
[0503] ESI-MS m/z: 297 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.24 (s, 3H), 4.51 (s, 2H), 5.09 (d, J=11.9 Hz, 1H), 5.55
(d, J=11.9 Hz, 1H), 7.11-7.04 (m, 3H), 7.34 (dd, J=7.7, 5.0 Hz,
1H), 7.86 (dd, J=7.7, 1.4 Hz, 1H), 8.58 (dd, J=5.0, 1.4 Hz,
1H).
INDUSTRIAL APPLICABILITY
[0504] According to the present invention, a tricyclic compound
having a PPAR .gamma. agonist activity, which is useful as an agent
for treating and/or preventing type 2 diabetes, impaired glucose
tolerance, insulin resistance syndrome, hypertension,
hyperlipidemia, metabolic syndrome, visceral obesity, obesity,
hypertriglyceridemia, inflammatory skin diseases, inflammatory
diseases, proliferative diseases, inflammatory neuropsychiatric
diseases, angiogenesis and pathological angiogenesis relating to
tumor growth and metastasis, neurodegenerative neuropsychiatric
diseases, cardiovascular diseases such as arteriosclerosis, cardiac
disease, cerebral apoplexy, renal diseases etc., or the like, or a
pharmaceutically acceptable salt thereof can be provided.
* * * * *